Honors & Awards

  • Glenn Award, Glenn Foundation for Medical Research (2015)
  • NIH Pioneer Award, NIH Director's Office/NIA (2015)
  • Transformative R01, NIH Director's Office/NIA (2013)
  • Senior Research Career Scientist, Veterans Administration (2012)
  • Distinguished Scholar Award, The John Douglas French Alzheimer’s Foundation (2005)
  • Zenith Award, Alzheimer's Association (2005)
  • Editor, Journal of Neuroinflammation (2004)
  • Medical and Scientific Advisory Council, Alzheimer's Association of Northern California & Northern Nevada (2004)

Professional Education

  • M.S., University of Bern, Switzerland, Microbiology (1989)
  • Ph.D., University of Bern, Switzerland, Immunology (1992)

Research & Scholarship

Current Research and Scholarly Interests

Our laboratory studies the role of immune and injury responses in neurodegeneration and Alzheimer’s disease. We seek to understand how immune responses and injury pathways may modulate neurodegeneration and age-related changes in the brain. We study these pathways in vivo and in cell culture using a number of genetic and proteomic tools. We have been particularly interested in the TGF-beta signaling pathway as a major regulator of biological processes and we are developing genetic and pharmacological agents to manipulate this pathway.


2017-18 Courses

Stanford Advisees

Graduate and Fellowship Programs


All Publications

  • Deficiency in Neuronal TGF-beta Signaling Leads to Nigrostriatal Degeneration and Activation of TGF-beta Signaling Protects against MPTP Neurotoxicity in Mice JOURNAL OF NEUROSCIENCE Tesseur, I., Nguyen, A., Chang, B., Li, L., Woodling, N. S., Wyss-Coray, T., Luo, J. 2017; 37 (17): 4584-4592


    Transforming growth factor-β (TGF-β) plays an important role in the development and maintenance of embryonic dopaminergic (DA) neurons in the midbrain. To study the function of TGF-β signaling in the adult nigrostriatal system, we generated transgenic mice with reduced TGF-β signaling in mature neurons. These mice display age-related motor deficits and degeneration of the nigrostriatal system. Increasing TGF-β signaling in the substantia nigra through adeno-associated virus expressing a constitutively active type I receptor significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and motor deficits. These results suggest that TGF-β signaling is critical for adult DA neuron survival and that modulating this signaling pathway has therapeutic potential in Parkinson disease.SIGNIFICANCE STATEMENT We show that reducing Transforming growth factor-β (TGF-β) signaling promotes Parkinson disease-related pathologies and motor deficits, and increasing TGF-β signaling reduces neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a parkinsonism-inducing agent. Our results provide a rationale to pursue a means of increasing TGF-β signaling as a potential therapy for Parkinson's disease.

    View details for DOI 10.1523/JNEUROSCI.2952-16.2017

    View details for Web of Science ID 000401038400014

    View details for PubMedID 28363982

  • Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer's pathology PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zhang, Z., Takeda-Uchimura, Y., Foyez, T., Ohtake-Niimi, S., Narentuya, Akatsu, H., Nishitsuji, K., Michikawa, M., Wyss-Coray, T., Kadomatsu, K., Uchimura, K. 2017; 114 (14): E2947-E2954


    We previously showed that microglial keratan sulfate (KS) was induced in amyotrophic lateral sclerosis. However, the functional roles of the glycan and its synthetic enzyme in neurodegenerative diseases, such as Alzheimer's disease (AD), a progressive disorder, are unclear. In our study, KS modified with sialic acids having a molecular mass of 125-220 kDa and the carbohydrate sulfotransferase GlcNAc6ST1 were up-regulated in the brains of two transgenic mouse models (J20 and Tg2576) and the brains of patients with AD. GlcNAc6ST1-deficient J20 (J20/GlcNAc6ST1(-/-)) mice demonstrated a complete absence of the microglial sialylated KS. J20/GlcNAc6ST1(-/-) primary microglia showed an increased level of amyloid-β phagocytosis and were hyperresponsive to interleukin 4, a potent antiinflammatory cytokine. Moreover, J20/GlcNAc6ST1(-/-) mice manifested reduced cerebral amyloid-β deposition. GlcNAc6ST1-synthesizing sialylated KS thus modulates AD pathology. Inhibition of KS synthesis by targeting GlcNAc6ST1 may therefore be beneficial for controlling AD pathogenesis.

    View details for DOI 10.1073/pnas.1615036114

    View details for Web of Science ID 000398159000019

    View details for PubMedID 28320965

  • Ageing, neurodegeneration and brain rejuvenation NATURE Wyss-Coray, T. 2016; 539 (7628): 180-186


    Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of the essence of being. Ageing, which is fundamental to neurodegeneration and dementia, affects every organ in the body and seems to be encoded partly in a blood-based signature. Indeed, factors in the circulation have been shown to modulate ageing and to rejuvenate numerous organs, including the brain. The discovery of such factors, the identification of their origins and a deeper understanding of their functions is ushering in a new era in ageing and dementia research.

    View details for DOI 10.1038/nature20411

    View details for Web of Science ID 000387318500028

    View details for PubMedID 27830812

    View details for PubMedCentralID PMC5172605

  • Traumatic Brain Injury Imaging in the Second Near-Infrared Window with a Molecular Fluorophore. Advanced materials Zhang, X., Wang, H., Antaris, A. L., Li, L., Diao, S., Ma, R., Nguyen, A., Hong, G., Ma, Z., Wang, J., Zhu, S., Castellano, J. M., Wyss-Coray, T., Liang, Y., Luo, J., Dai, H. 2016; 28 (32): 6872-6879


    Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. A bright, renal-excreted, and biocompatible near-infrared II fluorophore for in vivo imaging of TBI is designed. A transient hypoperfusion in the injured cerebral region, followed by fluorophore leakage, is observed. NIR-II fluorophores can provide noninvasive assessment of TBI.

    View details for DOI 10.1002/adma.201600706

    View details for PubMedID 27253071

  • In vivo assessment of behavioral recovery and circulatory exchange in the peritoneal parabiosis model SCIENTIFIC REPORTS Castellano, J. M., Palner, M., Li, S., Freeman, G. M., Andy Nguyen, A., Shen, B., Stan, T., Mosher, K. I., Chin, F. T., de Lecea, L., Luo, J., Wyss-Coray, T. 2016; 6


    The sharing of circulation between two animals using a surgical procedure known as parabiosis has created a wealth of information towards our understanding of physiology, most recently in the neuroscience arena. The systemic milieu is a complex reservoir of tissues, immune cells, and circulating molecules that is surprisingly not well understood in terms of its communication across organ systems. While the model has been used to probe complex physiological questions for many years, critical parameters of recovery and exchange kinetics remain incompletely characterized, limiting the ability to design experiments and interpret results for complex questions. Here we provide evidence that mice joined by parabiosis gradually recover much physiology relevant to the study of brain function. Specifically, we describe the timecourse for a variety of recovery parameters, including those for general health and metabolism, motor coordination, activity, and sleep behavior. Finally, we describe the kinetics of chimerism for several lymphocyte populations as well as the uptake of small molecules into the brains of mice following parabiosis. Our characterization provides an important resource to those attempting to understand the complex interplay between the immune system and the brain as well as other organ systems.

    View details for DOI 10.1038/srep29015

    View details for Web of Science ID 000378851500002

    View details for PubMedID 27364522

  • Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain MOLECULAR NEURODEGENERATION Jaeger, P. A., Lucin, K. M., Britschgi, M., Vardarajan, B., Huang, R., Kirby, E. D., Abbey, R., Boeve, B. F., Boxer, A. L., Farrer, L. A., Finch, N., Graff-Radford, N. R., Head, E., Hoffree, M., Huang, R., Johns, H., Karydas, A., Knopman, D. S., Loboda, A., Masliah, E., Narasimhan, R., Petersen, R. C., Podtelezhnikov, A., Pradhan, S., Rademakers, R., Sun, C., Younkin, S. G., Miller, B. L., Ideker, T., Wyss-Coray, T. 2016; 11


    Biological pathways that significantly contribute to sporadic Alzheimer's disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.To access this information we probed relative levels of close to 600 secreted signaling proteins from patients' blood samples using antibody microarrays and mapped disease-specific molecular networks. Using these networks as seeds we then employed independent genome and transcriptome data sets to corroborate potential pathogenic pathways.We identified Growth-Differentiation Factor (GDF) signaling as a novel Alzheimer's disease-relevant pathway supported by in vivo and in vitro follow-up experiments, demonstrating the existence of a highly informative link between cellular pathology and changes in circulatory signaling proteins.

    View details for DOI 10.1186/s13024-016-0095-2

    View details for Web of Science ID 000374728400001

    View details for PubMedID 27112350

  • Combined Plasma and Cerebrospinal Fluid Signature for the Prediction of Midterm Progression From Mild Cognitive Impairment to Alzheimer Disease JAMA NEUROLOGY Lehallier, B., Essioux, L., Gayan, J., Alexandridis, R., Nikolcheva, T., Wyss-Coray, T., Britschgi, M. 2016; 73 (2): 203-212
  • Beclin 1 regulates neuronal transforming growth factor-beta signaling by mediating recycling of the type I receptor ALK5 MOLECULAR NEURODEGENERATION O'Brien, C. E., Bonanno, L., Zhang, H., Wyss-Coray, T. 2015; 10

    View details for DOI 10.1186/s13024-015-0065-0

    View details for Web of Science ID 000366822900002

    View details for PubMedID 26692002

  • The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging COLD SPRING HARBOR PERSPECTIVES IN MEDICINE DeCarolis, N. A., Kirby, E. D., Wyss-Coray, T., Palmer, T. D. 2015; 5 (12)
  • Impact of peripheral myeloid cells on amyloid-ß pathology in Alzheimer's disease-like mice. journal of experimental medicine Prokop, S., Miller, K. R., Drost, N., Handrick, S., Mathur, V., Luo, J., Wegner, A., Wyss-Coray, T., Heppner, F. L. 2015; 212 (11): 1811-1818


    Although central nervous system-resident microglia are believed to be ineffective at phagocytosing and clearing amyloid-β (Aβ), a major pathological hallmark of Alzheimer's disease (AD), it has been suggested that peripheral myeloid cells constitute a heterogeneous cell population with greater Aβ-clearing capabilities. Here, we demonstrate that the conditional ablation of resident microglia in CD11b-HSVTK (TK) mice is followed by a rapid repopulation of the brain by peripherally derived myeloid cells. We used this system to directly assess the ability of peripheral macrophages to reduce Aβ plaque pathology and therefore depleted and replaced the pool of resident microglia with peripherally derived myeloid cells in Aβ-carrying APPPS1 mice crossed to TK mice (APPPS1;TK). Despite a nearly complete exchange of resident microglia with peripheral myeloid cells, there was no significant change in Aβ burden or APP processing in APPPS1;TK mice. Importantly, however, newly recruited peripheral myeloid cells failed to cluster around Aβ deposits. Even additional anti-Aβ antibody treatment aimed at engaging myeloid cells with amyloid plaques neither directed peripherally derived myeloid cells to amyloid plaques nor altered Aβ burden. These data demonstrate that mere recruitment of peripheral myeloid cells to the brain is insufficient in substantially clearing Aβ burden and suggest that specific additional triggers appear to be required to exploit the full potential of myeloid cell-based therapies for AD.

    View details for DOI 10.1084/jem.20150479

    View details for PubMedID 26458768

  • Blood-Borne Revitalization of the Aged Brain JAMA NEUROLOGY Castellano, J. M., Kirby, E. D., Wyss-Coray, T. 2015; 72 (10): 1191-1194


    In the modern medical era, more diverse and effective treatment options have translated to increased life expectancy. With this increased life span comes increased age-associated disease and the dire need to understand underlying causes so that therapies can be designed to mitigate the burden to health and the economy. Aging exacts a seemingly inevitable multisystem deterioration of function that acts as a risk factor for a variety of age-related disorders, including those that devastate organs of limited regenerative potential, such as the brain. Rather than studying the brain and mechanisms that govern its aging in isolation from other organ systems, an emerging approach is to understand the relatively unappreciated communication that exists between the brain and systemic environment. Revisiting classical methods of experimental physiology in animal models has uncovered surprising regenerative activity in young blood with translational implications for the aging liver, muscle, brain, and other organs. Soluble factors present in young or aged blood are sufficient to improve or impair cognitive function, respectively, suggesting an aging continuum of brain-relevant systemic factors. The age-associated plasma chemokine CCL11 has been shown to impair young brain function while GDF11 has been reported to increase the generation of neurons in aged mice. However, the identities of specific factors mediating memory-enhancing effects of young blood and their mechanisms of action are enigmatic. Here we review brain rejuvenation studies in the broader context of systemic rejuvenation research. We discuss putative mechanisms for blood-borne brain rejuvenation and suggest promising avenues for future research and development of therapies.

    View details for DOI 10.1001/jamaneurol.2015.1616

    View details for Web of Science ID 000362963000016

    View details for PubMedID 26237737

  • Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-beta signaling and astrocyte functions NATURE NEUROSCIENCE Schachtrup, C., Ryu, J. K., Mammadzada, K., Khan, A. S., Carlton, P. M., Perez, A., Christian, F., Le Moan, N., Vagena, E., Baeza-Raja, B., Rafalski, V., Chan, J. P., Nitschke, R., Houslay, M. D., Ellisman, M. H., Wyss-Coray, T., Palop, J. J., Akassoglou, K. 2015; 18 (8): 1077-?

    View details for DOI 10.1038/nn.4054

    View details for Web of Science ID 000358605400006

  • beta 2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis NATURE MEDICINE Smith, L. K., He, Y., Park, J., Bieri, G., Snethlage, C. E., Lin, K., Gontier, G., Wabl, R., Plambeck, K. E., Udeochu, J., Wheatley, E. G., Bouchard, J., Eggel, A., Narasimha, R., Grant, J. L., Luo, J., Wyss-Coray, T., Villeda, S. A. 2015; 21 (8): 932-937


    Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

    View details for DOI 10.1038/nm.3898

    View details for Web of Science ID 000359181000021

    View details for PubMedID 26147761

    View details for PubMedCentralID PMC4529371

  • Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-ß signaling and astrocyte functions. Nature neuroscience Schachtrup, C., Ryu, J. K., Mammadzada, K., Khan, A. S., Carlton, P. M., Perez, A., Christian, F., Le Moan, N., Vagena, E., Baeza-Raja, B., Rafalski, V., Chan, J. P., Nitschke, R., Houslay, M. D., Ellisman, M. H., Wyss-Coray, T., Palop, J. J., Akassoglou, K. 2015; 18 (8): 1077-1080


    Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotrophin receptor (p75(NTR)) is a component of the nuclear pore complex (NPC) required for glial scar formation and reduced gamma oscillations in mice via regulation of transforming growth factor (TGF)-β signaling. Cleaved p75(NTR) interacts with nucleoporins to promote Smad2 nucleocytoplasmic shuttling. Thus, NPC remodeling by regulated intramembrane cleavage of p75(NTR) controls astrocyte-neuronal communication in response to profibrotic factors.

    View details for DOI 10.1038/nn.4054

    View details for PubMedID 26120963

  • Go with your gut: microbiota meet microglia. Nature neuroscience Mosher, K. I., Wyss-Coray, T. 2015; 18 (7): 930-931

    View details for DOI 10.1038/nn.4051

    View details for PubMedID 26108718

  • CalFluors: A Universal Motif for Fluorogenic Azide Probes across the Visible Spectrum JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Shieh, P., Dien, V. T., Beahm, B. J., Castellano, J. M., Wyss-Coray, T., Bertozzi, C. R. 2015; 137 (22): 7145-7151


    Fluorescent bioorthogonal smart probes across the visible spectrum will enable sensitive visualization of metabolically labeled molecules in biological systems. Here we present a unified design, based on the principle of photoinduced electron transfer, to access a panel of highly fluorogenic azide probes that are activated by conversion to the corresponding triazoles via click chemistry. Termed the CalFluors, these probes possess emission maxima that range from green to far red wavelengths, and enable sensitive biomolecule detection under no-wash conditions. We used the CalFluor probes to image various alkyne-labeled biomolecules (glycans, DNA, RNA, and proteins) in cells, developing zebrafish, and mouse brain tissue slices.

    View details for DOI 10.1021/jacs.5b02383

    View details for Web of Science ID 000356322300038

    View details for PubMedID 25902190

  • Astrocyte-Derived TGF-beta 1 Accelerates Disease Progression in ALS Mice by Interfering with the Neuroprotective Functions of Microglia and T Cells CELL REPORTS Endo, F., Komine, O., Fujimori-Tonou, N., Katsuno, M., Jin, S., Watanabe, S., Sobue, G., Dezawa, M., Wyss-Coray, T., Yamanaka, K. 2015; 11 (4): 592-604


    Neuroinflammation, which includes both neuroprotective and neurotoxic reactions by activated glial cells and infiltrated immune cells, is involved in the pathomechanism of amyotrophic lateral sclerosis (ALS). However, the cytokines that regulate the neuroprotective inflammatory response in ALS are not clear. Here, we identify transforming growth factor-β1 (TGF-β1), which is upregulated in astrocytes of murine and human ALS, as a negative regulator of neuroprotective inflammatory response. We demonstrate that astrocyte-specific overproduction of TGF-β1 in SOD1(G93A) mice accelerates disease progression in a non-cell-autonomous manner, with reduced IGF-I production in deactivated microglia and fewer T cells with an IFN-γ-dominant milieu. Moreover, expression levels of endogenous TGF-β1 in SOD1(G93A) mice negatively correlate with lifespan. Furthermore, pharmacological administration of a TGF-β signaling inhibitor after disease onset extends survival time of SOD1(G93A) mice. These findings indicate that astrocytic TGF-β1 determines disease progression and is critical to the pathomechanism of ALS.

    View details for DOI 10.1016/j.celrep.2015.03.053

    View details for Web of Science ID 000353902600009

    View details for PubMedID 25892237

  • Neuroinflammation in Alzheimer's disease LANCET NEUROLOGY Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., Herrup, K., Frautschy, S. A., Finsen, B., Brown, G. C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E., Halle, A., Petzold, G. C., Town, T., Morgan, D., Shinohara, M. L., Perry, V. H., Holmes, C., Bazan, N. G., Brooks, D. J., Hunot, S., Joseph, B., Deigendesch, N., Garaschuk, O., Boddeke, E., Dinarello, C. A., Breitner, J. C., Cole, G. M., Golenbock, D. T., Kummer, M. P. 2015; 14 (4): 388-405
  • Neuroinflammation in Alzheimer's disease. The Lancet. Neurology Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., Herrup, K., Frautschy, S. A., Finsen, B., Brown, G. C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E., Halle, A., Petzold, G. C., Town, T., Morgan, D., Shinohara, M. L., Perry, V. H., Holmes, C., Bazan, N. G., Brooks, D. J., Hunot, S., Joseph, B., Deigendesch, N., Garaschuk, O., Boddeke, E., Dinarello, C. A., Breitner, J. C., Cole, G. M., Golenbock, D. T., Kummer, M. P. 2015; 14 (4): 388-405


    Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

    View details for DOI 10.1016/S1474-4422(15)70016-5

    View details for PubMedID 25792098

  • Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kirby, E. D., Kuwahara, A. A., Messer, R. L., Wyss-Coray, T. 2015; 112 (13): 4128-4133


    The adult hippocampus hosts a population of neural stem and progenitor cells (NSPCs) that proliferates throughout the mammalian life span. To date, the new neurons derived from NSPCs have been the primary measure of their functional relevance. However, recent studies show that undifferentiated cells may shape their environment through secreted growth factors. Whether endogenous adult NSPCs secrete functionally relevant growth factors remains unclear. We show that adult hippocampal NSPCs secrete surprisingly large quantities of the essential growth factor VEGF in vitro and in vivo. This self-derived VEGF is functionally relevant for maintaining the neurogenic niche as inducible, NSPC-specific loss of VEGF results in impaired stem cell maintenance despite the presence of VEGF produced from other niche cell types. These findings reveal adult hippocampal NSPCs as an unanticipated source of an essential growth factor and imply an exciting functional role for adult brain NSPCs as secretory cells.

    View details for DOI 10.1073/pnas.1422448112

    View details for Web of Science ID 000351914500079

    View details for PubMedID 25775598

  • PET Imaging of Translocator Protein (18 kDa) in a Mouse Model of Alzheimer's Disease Using N-(2,5-Dimethoxybenzyl)-2-18F-Fluoro-N-(2-Phenoxyphenyl)Acetamide. Journal of nuclear medicine : official publication, Society of Nuclear Medicine James, M. L., Belichenko, N. P., Nguyen, T. V., Andrews, L. E., Ding, Z., Liu, H., Bodapati, D., Arksey, N., Shen, B., Cheng, Z., Wyss-Coray, T., Gambhir, S. S., Longo, F. M., Chin, F. T. 2015; 56 (2): 311-316


    Herein we aimed to evaluate the utility of N-(2,5-dimethoxybenzyl)-2-(18)F-fluoro-N-(2-phenoxyphenyl)acetamide ((18)F-PBR06) for detecting alterations in translocator protein (TSPO) (18 kDa), a biomarker of microglial activation, in a mouse model of Alzheimer's disease (AD).Wild-type (wt) and AD mice (i.e., APP(L/S)) underwent (18)F-PBR06 PET imaging at predetermined time points between the ages of 5-6 and 15-16 mo. MR images were fused with PET/CT data to quantify (18)F-PBR06 uptake in the hippocampus and cortex. Ex vivo autoradiography and TSPO/CD68 immunostaining were also performed using brain tissue from these mice.PET images showed significantly higher accumulation of (18)F-PBR06 in the cortex and hippocampus of 15- to 16-mo-old APP(L/S) mice than age-matched wts (cortex/muscle: 2.43 ± 0.19 vs. 1.55 ± 0.15, P < 0.005; hippocampus/muscle: 2.41 ± 0.13 vs. 1.55 ± 0.12, P < 0.005). And although no significant difference was found between wt and APP(L/S) mice aged 9-10 mo or less using PET (P = 0.64), we were able to visualize and quantify a significant difference in (18)F-PBR06 uptake in these mice using autoradiography (cortex/striatum: 1.13 ± 0.04 vs. 0.96 ± 0.01, P < 0.05; hippocampus/striatum: 1.266 ± 0.003 vs. 1.096 ± 0.017, P < 0.001). PET results for 15- to 16-mo-old mice correlated well with autoradiography and immunostaining (i.e., increased (18)F-PBR06 uptake in brain regions containing elevated CD68 and TSPO staining in APP(L/S) mice, compared with wts).(18)F-PBR06 shows great potential as a tool for visualizing TSPO/microglia in the progression and treatment of AD.

    View details for DOI 10.2967/jnumed.114.141648

    View details for PubMedID 25613536

  • Beclin 1 regulates neuronal transforming growth factor-ß signaling by mediating recycling of the type I receptor ALK5. Molecular neurodegeneration O'Brien, C. E., Bonanno, L., Zhang, H., Wyss-Coray, T. 2015; 10 (1): 69-?


    Beclin 1 is a key regulator of multiple trafficking pathways, including autophagy and receptor recycling in yeast and microglia. Decreased beclin 1 levels in the CNS result in neurodegeneration, an effect attributed to impaired autophagy. However, neurons also rely heavily on trophic factors, and signaling through these pathways requires the proper trafficking of trophic factor receptors.We discovered that beclin 1 regulates signaling through the neuroprotective TGF-β pathway. Beclin 1 is required for recycling of the type I TGF-β receptor ALK5. We show that beclin 1 recruits the retromer to ALK5 and facilitates its localization to Rab11(+) endosomes. Decreased levels of beclin 1, or its binding partners VPS34 and UVRAG, impair TGF-β signaling.These findings identify beclin 1 as a positive regulator of a trophic signaling pathway via receptor recycling, and suggest that neuronal death induced by decreased beclin 1 levels may also be due to impaired trophic factor signaling.

    View details for DOI 10.1186/s13024-015-0065-0

    View details for PubMedID 26692002

    View details for PubMedCentralID PMC4687091

  • The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging. Cold Spring Harbor perspectives in medicine DeCarolis, N. A., Kirby, E. D., Wyss-Coray, T., Palmer, T. D. 2015; 5 (12)


    Aging is strongly correlated with decreases in neurogenesis, the process by which neural stem and progenitor cells proliferate and differentiate into new neurons. In addition to stem-cell-intrinsic factors that change within the aging stem-cell pool, recent evidence emphasizes new roles for systemic and microenvironmental factors in modulating the neurogenic niche. This article focuses on new insights gained through the use of heterochronic parabiosis models, in which an old mouse and a young circulatory system are joined. By studying the brains of both young and old mice, researchers are beginning to uncover circulating proneurogenic "youthful" factors and "aging" factors that decrease stem-cell activity and neurogenesis. Ultimately, the identification of factors that influence stem-cell aging may lead to strategies that slow or even reverse age-related decreases in neural-stem-cell (NSC) function and neurogenesis.

    View details for DOI 10.1101/cshperspect.a025874

    View details for PubMedID 26627453

  • Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome PAIN Li, W., Guo, T., Shi, X., Czirr, E., Stan, T., Sahbaie, P., Wyss-Coray, T., Kingery, W. S., Clark, J. D. 2014; 155 (11): 2377-2389
  • Aging-induced type I interferon response at the choroid plexus negatively affects brain function SCIENCE Baruch, K., Deczkowska, A., David, E., Castellano, J. M., Miller, O., Kertser, A., Berkutzki, T., Barnett-Itzhaki, Z., Bezalel, D., Wyss-Coray, T., Amit, I., Schwartz, M. 2014; 346 (6205): 89-93
  • Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science Baruch, K., Deczkowska, A., David, E., Castellano, J. M., Miller, O., Kertser, A., Berkutzki, T., Barnett-Itzhaki, Z., Bezalel, D., Wyss-Coray, T., Amit, I., Schwartz, M. 2014; 346 (6205): 89-93


    Aging-associated cognitive decline is affected by factors produced inside and outside the brain. By using multiorgan genome-wide analysis of aged mice, we found that the choroid plexus, an interface between the brain and the circulation, shows a type I interferon (IFN-I)-dependent gene expression profile that was also found in aged human brains. In aged mice, this response was induced by brain-derived signals, present in the cerebrospinal fluid. Blocking IFN-I signaling within the aged brain partially restored cognitive function and hippocampal neurogenesis and reestablished IFN-II-dependent choroid plexus activity, which is lost in aging. Our data identify a chronic aging-induced IFN-I signature, often associated with antiviral response, at the brain's choroid plexus and demonstrate its negative influence on brain function, thereby suggesting a target for ameliorating cognitive decline in aging.

    View details for DOI 10.1126/science.1252945

    View details for PubMedID 25147279

  • Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function JAMA NEUROLOGY Mak, A. C., Pullinger, C. R., Tang, L. F., Wong, J. S., Deo, R. C., Schwarz, J., Gugliucci, A., Movsesyan, I., Ishida, B. Y., Chu, C., Poon, A., Kim, P., Stock, E. O., Schaefer, E. J., Asztalos, B. F., Castellano, J. M., Wyss-Coray, T., Duncan, J. L., Miller, B. L., Kane, J. P., Kwok, P., Malloy, M. J. 2014; 71 (10): 1228-1236
  • Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA neurology Mak, A. C., Pullinger, C. R., Tang, L. F., Wong, J. S., Deo, R. C., Schwarz, J., Gugliucci, A., Movsesyan, I., Ishida, B. Y., Chu, C., Poon, A., Kim, P., Stock, E. O., Schaefer, E. J., Asztalos, B. F., Castellano, J. M., Wyss-Coray, T., Duncan, J. L., Miller, B. L., Kane, J. P., Kwok, P., Malloy, M. J. 2014; 71 (10): 1228-1236


    The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE).To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism.Whole-exome sequencing was performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants.Whole-exome sequencing, lipoprotein analysis, and neurocognitive function.The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally.Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.

    View details for DOI 10.1001/jamaneurol.2014.2011

    View details for PubMedID 25111166

  • TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis SCIENCE TRANSLATIONAL MEDICINE Kleinberger, G., Yamanishi, Y., Suarez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., Tahirovic, S., Lleo, A., Alcolea, D., Fortea, J., Willem, M., Lammich, S., Molinuevo, J. L., Sanchez-Valle, R., Antonell, A., Ramirez, A., Heneka, M. T., Sleegers, K., van der Zee, J., Martin, J., Engelborghs, S., Demirtas-Tatlidede, A., Zetterberg, H., Van Broeckhoven, C., Gurvit, H., Wyss-Coray, T., Hardy, J., Colonna, M., Haass, C. 2014; 6 (243)


    Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.

    View details for DOI 10.1126/scitranslmed.3009093

    View details for Web of Science ID 000338712200006

    View details for PubMedID 24990881

  • ALK5-dependent TGF-beta signaling is a major determinant of late-stage adult neurogenesis NATURE NEUROSCIENCE He, Y., Zhang, H., Yung, A., Villeda, S. A., Jaeger, P. A., Olayiwola, O., Fainberg, N., Wyss-Coray, T. 2014; 17 (7): 943-952


    The transforming growth factor-β (TGF-β) signaling pathway serves critical functions in CNS development, but, apart from its proposed neuroprotective actions, its physiological role in the adult brain is unclear. We observed a prominent activation of TGF-β signaling in the adult dentate gyrus and expression of downstream Smad proteins in this neurogenic zone. Consistent with a function of TGF-β signaling in adult neurogenesis, genetic deletion of the TGF-β receptor ALK5 reduced the number, migration and dendritic arborization of newborn neurons. Conversely, constitutive activation of neuronal ALK5 in forebrain caused a marked increase in these aspects of neurogenesis and was associated with higher expression of c-Fos in newborn neurons and with stronger memory function. Our findings describe an unexpected role for ALK5-dependent TGF-β signaling as a regulator of the late stages of adult hippocampal neurogenesis, which may have implications for changes in neurogenesis during aging and disease.

    View details for DOI 10.1038/nn.3732

    View details for Web of Science ID 000338097200011

    View details for PubMedID 24859199

  • Stem cells as vehicles for youthful regeneration of aged tissues. journals of gerontology. Series A, Biological sciences and medical sciences Rando, T. A., Wyss-Coray, T. 2014; 69: S39-42


    Stem cells hold great promise for regenerative therapies for a wide spectrum of diseases and disorders of aging by virtue of their ability to regenerate tissues and contribute to their homeostasis. Aging is associated with a marked decline in these functionalities of adult stem cells. As such, regeneration of aged tissues is both less efficient and less effective than that of young tissues. Recent studies have revealed the remarkably dynamic responses of stem cells to systemic signals, including the ability of "youthful" factors in the blood of young animals to enhance the functionality of aged stem cells. Thus, there is much hope that even aged stem cells retain a remarkable regenerative potential if provided with the correct cues and environment to engage in tissue repair. The overall focus of the presentations of this session is to address the determinants of changes in stem cell functionality with age, the key characteristics of stem cells in aged tissues, the extent to which those characteristics are capable of being rejuvenated and by what signals, and the potential for stem cell therapeutics for chronic diseases and acute injuries in aged individuals.

    View details for DOI 10.1093/gerona/glu043

    View details for PubMedID 24833585

    View details for PubMedCentralID PMC4022127

  • Stem cells as vehicles for youthful regeneration of aged tissues. journals of gerontology. Series A, Biological sciences and medical sciences Rando, T. A., Wyss-Coray, T. 2014; 69: S39-42

    View details for DOI 10.1093/gerona/glu043

    View details for PubMedID 24833585

  • Sorting Through the Roles of Beclin 1 in Microglia and Neurodegeneration JOURNAL OF NEUROIMMUNE PHARMACOLOGY O'Brien, C. E., Wyss-Coray, T. 2014; 9 (3): 285-292


    Beclin 1 has a well-established role in regulating autophagy, a cellular degradation pathway. Although the yeast ortholog of beclin 1 (Atg6/Vps30) was discovered to also regulate vacuolar protein sorting nearly 30 years ago, the varied functions of beclin 1 in mammalian cells are only beginning to be sorted out. We recently described a role for beclin 1 in regulating recycling of phagocytic receptors in microglia, a function analogous to that of its yeast ortholog. Microglia lacking beclin 1 have a reduced phagocytic capacity, which impairs clearance of amyloid β (Aβ) in a mouse model of Alzheimer's Disease (AD). Here we summarize these findings and discuss the implications for beclin 1-regulated receptor recycling in neurodegenerative disease.

    View details for DOI 10.1007/s11481-013-9519-8

    View details for Web of Science ID 000335671000003

    View details for PubMedID 24385262

    View details for PubMedCentralID PMC4019692

  • Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature medicine Villeda, S. A., Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., Smith, L. K., Bieri, G., Lin, K., Berdnik, D., Wabl, R., Udeochu, J., Wheatley, E. G., Zou, B., Simmons, D. A., Xie, X. S., Longo, F. M., Wyss-Coray, T. 2014; 20 (6): 659-663


    As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

    View details for DOI 10.1038/nm.3569

    View details for PubMedID 24793238

    View details for PubMedCentralID PMC4224436

  • Noninvasive in vivo monitoring of tissue-specific global gene expression in humans. Proceedings of the National Academy of Sciences of the United States of America Koh, W., Pan, W., Gawad, C., Fan, H. C., Kerchner, G. A., Wyss-Coray, T., Blumenfeld, Y. J., El-Sayed, Y. Y., Quake, S. R. 2014; 111 (20): 7361-7366


    Circulating cell-free RNA in the blood provides a potential window into the health, phenotype, and developmental programs of a variety of human organs. We used high-throughput methods of RNA analysis such as microarrays and next-generation sequencing to characterize the global landscape circulating RNA in a cohort of human subjects. By focusing on genes whose expression is highly specific to certain tissues, we were able to identify the relative contributions of these tissues to circulating RNA and to monitor changes in tissue development and health. As one application of this approach, we performed a longitudinal study on pregnant women and analyzed their combined cell-free RNA transcriptomes across all three trimesters of pregnancy and after delivery. In addition to the analysis of mRNA, we observed and characterized noncoding species such as long noncoding RNA and circular RNA transcripts whose presence had not been previously observed in human plasma. We demonstrate that it is possible to track specific longitudinal phenotypic changes in both the mother and the fetus and that it is possible to directly measure transcripts from a variety of fetal tissues in the maternal blood sample. We also studied the role of neuron-specific transcripts in the blood of healthy adults and those suffering from the neurodegenerative disorder Alzheimer's disease and showed that disease specific neural transcripts are present at increased levels in the blood of affected individuals. Characterization of the cell-free transcriptome in its entirety may thus provide broad insights into human health and development without the need for invasive tissue sampling.

    View details for DOI 10.1073/pnas.1405528111

    View details for PubMedID 24799715

  • Microglial dysfunction in brain aging and Alzheimer's disease BIOCHEMICAL PHARMACOLOGY Mosher, K. I., Wyss-Coray, T. 2014; 88 (4): 594-604


    Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer's disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore, microglial "activation" and "neuroinflammation" are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.

    View details for DOI 10.1016/j.bcp.2014.01.008

    View details for Web of Science ID 000334977400018

    View details for PubMedID 24445162

  • APOE {varepsilon}4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory. Neurology Kerchner, G. A., Berdnik, D., Shen, J. C., Bernstein, J. D., Fenesy, M. C., Deutsch, G. K., Wyss-Coray, T., Rutt, B. K. 2014; 82 (8): 691-697


    Using high-resolution structural MRI, we endeavored to study the relationships among APOE ε4, hippocampal subfield and stratal anatomy, and episodic memory.Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE ε4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment.We found a selective, dose-dependent association of APOE ε4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the ε4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE ε4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE ε4 allele to its phenotypic effects on memory.The APOE ε4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation.

    View details for DOI 10.1212/WNL.0000000000000154

    View details for PubMedID 24453080

  • Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation. journal of experimental medicine Ding, Z., Mathur, V., Ho, P. P., James, M. L., Lucin, K. M., Hoehne, A., Alabsi, H., Gambhir, S. S., Steinman, L., Luo, J., Wyss-Coray, T. 2014; 211 (2): 189-198


    Aberrant microglial responses contribute to neuroinflammation in many neurodegenerative diseases, but no current therapies target pathogenic microglia. We discovered unexpectedly that the antiviral drug ganciclovir (GCV) inhibits the proliferation of microglia in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), as well as in kainic acid-induced excitotoxicity. In EAE, GCV largely prevented infiltration of T lymphocytes into the central nervous system (CNS) and drastically reduced disease incidence and severity when delivered before the onset of disease. In contrast, GCV treatment had minimal effects on peripheral leukocyte distribution in EAE and did not inhibit generation of antibodies after immunization with ovalbumin. Additionally, a radiolabeled analogue of penciclovir, [(18)F]FHBG, which is similar in structure to GCV, was retained in areas of CNS inflammation in EAE, but not in naive control mice, consistent with the observed therapeutic effects. Our experiments suggest GCV may have beneficial effects in the CNS beyond its antiviral properties.

    View details for DOI 10.1084/jem.20120696

    View details for PubMedID 24493798

    View details for PubMedCentralID PMC3920559

  • The future of blood-based biomarkers for Alzheimer's disease ALZHEIMERS & DEMENTIA Henriksen, K., O'Bryant, S. E., Hamper, H., Trojanowski, J. Q., Montine, T. J., Jeromin, A., Blennow, K., Lonneborg, A., Wyss-Coray, T., Soares, H., Bazenet, C., Sjogren, M., Hu, W., Lovestone, S., Karsdal, M. A., Weiner, M. W. 2014; 10 (1): 115-131


    Treatment of Alzheimer's disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the "right" control population, and the blood-brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.

    View details for DOI 10.1016/j.jalz.2013.01.013

    View details for Web of Science ID 000329559300015

    View details for PubMedID 23850333

  • Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury FRONTIERS IN NEUROLOGY Luo, J., Nguyen, A., Villeda, S., Zhang, H., Ding, Z., Lindsey, D., Bieri, G., Castellano, J. M., Beaupre, G. S., Wyss-Coray, T. 2014; 5
  • Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AßPP(L/S) transgenic mice. Journal of Alzheimer's disease : JAD Nguyen, T. V., Shen, L., Vander Griend, L., Quach, L. N., Belichenko, N. P., Saw, N., Yang, T., Shamloo, M., Wyss-Coray, T., Massa, S. M., Longo, F. M. 2014; 42 (2): 459-483


    The p75 neurotrophin receptor (p75NTR) is involved in degenerative mechanisms related to Alzheimer's disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach. Prior studies indicated that the non-peptide, small molecule p75NTR ligands LM11A-31, and chemically unrelated LM11A-24, could block amyloid-β-induced deleterious signaling and neurodegeneration in vitro, and LM11A-31 was found to mitigate neuritic degeneration and behavioral deficits in a mouse model of AD. In this study, we determined whether these in vivo findings represent class effects of p75NTR ligands by examining LM11A-24 effects. In addition, the range of compound effects was further examined by evaluating tau pathology and neuroinflammation. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance, while both ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds.

    View details for DOI 10.3233/JAD-140036

    View details for PubMedID 24898660

  • Small Molecule p75(NTR) Ligands Reduce Pathological Phosphorylation and Misfolding of Tau, Inflammatory Changes, Cholinergic Degeneration, and Cognitive Deficits in A beta PPL/S Transgenic Mice JOURNAL OF ALZHEIMERS DISEASE Nguyen, T. V., Shen, L., Vander Griend, L., Quach, L. N., Belichenko, N. P., Saw, N., Yang, T., Shamloo, M., Wyss-Coray, T., Massa, S. M., Longo, F. M. 2014; 42 (2): 459-483


    The p75 neurotrophin receptor (p75NTR) is involved in degenerative mechanisms related to Alzheimer's disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach. Prior studies indicated that the non-peptide, small molecule p75NTR ligands LM11A-31, and chemically unrelated LM11A-24, could block amyloid-β-induced deleterious signaling and neurodegeneration in vitro, and LM11A-31 was found to mitigate neuritic degeneration and behavioral deficits in a mouse model of AD. In this study, we determined whether these in vivo findings represent class effects of p75NTR ligands by examining LM11A-24 effects. In addition, the range of compound effects was further examined by evaluating tau pathology and neuroinflammation. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance, while both ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds.

    View details for DOI 10.3233/JAD-140036

    View details for Web of Science ID 000341572000012

  • Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury. Frontiers in neurology Luo, J., Nguyen, A., Villeda, S., Zhang, H., Ding, Z., Lindsey, D., Bieri, G., Castellano, J. M., Beaupre, G. S., Wyss-Coray, T. 2014; 5: 12-?


    Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all traumatic brain injuries. The consequences of repetitive mTBI have become of particular concern for individuals engaged in certain sports or in military operations. Many mTBI patients suffer long-lasting neurobehavioral impairments. In order to expedite pre-clinical research and therapy development, there is a need for animal models that reflect the long-term cognitive and pathological features seen in patients. In the present study, we developed and characterized a mouse model of repetitive mTBI, induced onto the closed head over the left frontal hemisphere with an electromagnetic stereotaxic impact device. Using GFAP-luciferase bioluminescence reporter mice that provide a readout of astrocyte activation, we observed an increase in bioluminescence relative to the force delivered by the impactor after single impact and cumulative effects of repetitive mTBI. Using the injury parameters established in the reporter mice, we induced a repetitive mTBI in wild-type C57BL/6J mice and characterized the long-term outcome. Animals received repetitive mTBI showed a significant impairment in spatial learning and memory when tested at 2 and 6 months after injury. A robust astrogliosis and increased p-Tau immunoreactivity were observed upon post-mortem pathological examinations. These findings are consistent with the deficits and pathology associated with mTBI in humans and support the use of this model to evaluate potential therapeutic approaches.

    View details for DOI 10.3389/fneur.2014.00012

    View details for PubMedID 24550885

    View details for PubMedCentralID PMC3912443

  • A revival of parabiosis in biomedical research. Swiss medical weekly Eggel, A., Wyss-Coray, T. 2014; 144: w13914-?


    Modern medicine wields the power to treat large numbers of diseases and injuries most of us would have died from just a hundred years ago, yet many of the most devastating diseases of our time are still untreatable. Chronic conditions of age such as cardiovascular disease, diabetes, osteoarthritis or Alzheimer's disease turn out to be of a complexity that may require transformative ideas and paradigms to understand and treat them. Parabiosis, which is characterised by a shared blood supply between two surgically connected animals, may just provide such a transformative experimental paradigm. Although forgotten and shunned now in many countries, it has contributed to major breakthroughs in tumour biology, endocrinology and transplantation research in the past century. Interestingly, recent studies from the United States and Britain are reporting stunning advances in stem cell biology and tissue regeneration using parabiosis between young and old mice, indicating a possible revival of this paradigm. We review here briefly the history of parabiosis and discuss its utility to study physiological and pathophysiological processes. We argue that parabiosis is a technique that should enjoy wider acceptance and application, and that policies should be revisited to allow its use in biomedical research.

    View details for DOI 10.4414/smw.2014.13914

    View details for PubMedID 24496774

  • Chronic Over-Expression of TGF beta 1 Alters Hippocampal Structure and Causes Learning Deficits HIPPOCAMPUS Martinez-Canabal, A., Wheeler, A. L., Sarkis, D., Lerch, J. P., Lu, W., Buckwalter, M. S., Wyss-Coray, T., Josselyn, S. A., Frankland, P. W. 2013; 23 (12): 1198-1211


    The cytokine Transforming Growth Factor β1 (TGFβ1) is chronically upregulated in several neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis and multiple sclerosis, and following stroke. While previous studies have shown that TGFβ1 may be neuroprotective, chronic exposure to elevated levels of this cytokine may contribute to disease pathology on its own. In order to study the effects of chronic exposure to TGFβ1 in isolation we used transgenic mice that over-express a constitutively active porcine TGFβ1 in astrocytes. We found that TGFβ1 over-expression altered brain structure, with the most pronounced volumetric increases localized to the hippocampus. Within the dentate gyrus (DG) of the hippocampus, increases in granule cell number and astrocyte size were responsible for volumetric expansion, with the increased granule cell number primarily related to a marked reduction in death of new granule cells generated in adulthood. Finally, these cumulative changes in DG micro- and macrostructure were associated with the age-dependent emergence of spatial learning deficits in TGFβ1 over-expressing mice. Together, our data indicate that chronic upregulation of TGFβ1 negatively impacts hippocampal structure and, even in the absence of disease, impairs hippocampus-dependent learning. © 2013 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hipo.22159

    View details for Web of Science ID 000327157200007

    View details for PubMedID 23804429

  • Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron Lucin, K. M., O'Brien, C. E., Bieri, G., Czirr, E., Mosher, K. I., Abbey, R. J., Mastroeni, D. F., Rogers, J., Spencer, B., Masliah, E., Wyss-Coray, T. 2013; 79 (5): 873-886


    Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer's disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD.

    View details for DOI 10.1016/j.neuron.2013.06.046

    View details for PubMedID 24012002

    View details for PubMedCentralID PMC3779465

  • Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron Lucin, K. M., O'Brien, C. E., Bieri, G., Czirr, E., Mosher, K. I., Abbey, R. J., Mastroeni, D. F., Rogers, J., Spencer, B., Masliah, E., Wyss-Coray, T. 2013; 79 (5): 873-886


    Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer's disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD.

    View details for DOI 10.1016/j.neuron.2013.06.046

    View details for PubMedID 24012002

    View details for PubMedCentralID PMC3779465

  • TDP-43 frontotemporal lobar degeneration and autoimmune disease JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Miller, Z. A., Rankin, K. P., Graff-Radford, N. R., Takada, L. T., Sturm, V. E., Cleveland, C. M., Criswell, L. A., Jaeger, P. A., Stan, T., Heggeli, K. A., Hsu, S. C., Karydas, A., Khan, B. K., Grinberg, L. T., Gorno-Tempini, M. L., Boxer, A. L., Rosen, H. J., Kramer, J. H., Coppola, G., Geschwind, D. H., Rademakers, R., Seeley, W. W., Wyss-Coray, T., Miller, B. L. 2013; 84 (9): 956-962


    BACKGROUND: The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored. OBJECTIVE: To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared with neurologically healthy normal controls (NC) and Alzheimer's disease (AD) as dementia controls. DESIGN: Case control. SETTING: Academic medical centres. PARTICIPANTS: 129 svPPA, 39 PGRN, 186 NC and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN and NC cohorts underwent serum analysis for tumour necrosis factor α (TNF-α) levels. OUTCOME MEASURES: χ(2) Comparison of autoimmune prevalence and follow-up logistic regression. RESULTS: There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared with NC. CONCLUSIONS: svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared with NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 aggregation.

    View details for DOI 10.1136/jnnp-2012-304644

    View details for Web of Science ID 000323164000007

    View details for PubMedID 23543794

  • A small molecule p75(NTR) ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model. Neurobiology of aging Knowles, J. K., Simmons, D. A., Nguyen, T. V., Vander Griend, L., Xie, Y., Zhang, H., Yang, T., Pollak, J., Chang, T., Arancio, O., Buckwalter, M. S., Wyss-Coray, T., Massa, S. M., Longo, F. M. 2013; 34 (8): 2052-2063


    The p75 neurotrophin receptor (p75(NTR)) is associated with multiple mechanisms linked to Alzheimer's disease (AD); hence, modulating its function might confer therapeutic effects. In previous in vitro work, we developed small molecule p75(NTR) ligands that inhibited amyloid-β-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75(NTR) ligand, LM11A-31, was administered orally to the Thy-1 hAPP(Lond/Swe) (APP(L/S)) AD mouse model. LM11A-31 reached brain concentrations known to inhibit degenerative signaling without toxicity or induction of hyperalgesia. It prevented deficits in novel object recognition after 2.5 months and, in a separate cohort, deficits in Y-maze performance after 3 months of treatment. Stereology studies found that the number and size of basal forebrain cholinergic neurons, which are normal in APP(L/S) mice, were unaffected. Neuritic dystrophy, however, was readily apparent in the basal forebrain, hippocampus and cortex, and was significantly reduced by LM11A-31, with no effect on amyloid levels. These studies reveal that p75(NTR) is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates.

    View details for DOI 10.1016/j.neurobiolaging.2013.02.015

    View details for PubMedID 23545424

  • Targeting autophagy for disease therapy. Nature biotechnology Lucin, K. M., Wyss-Coray, T. 2013; 31 (4): 322-323

    View details for DOI 10.1038/nbt.2554

    View details for PubMedID 23563430

  • The circulatory systemic environment as a modulator of neurogenesis and brain aging. Autoimmunity reviews Villeda, S. A., Wyss-Coray, T. 2013; 12 (6): 674-677


    The ability of the adult brain to generate newly born neurons dramatically declines during aging, and has even been proposed to contribute, in part, to age-related cognitive impairments. While intrinsic molecular mechanisms underlying decreased neurogenesis during aging have begun to be elucidated, relatively little is still known as to the contribution of the systemic environment. Interestingly, immune signaling has quickly emerged as a key negative regulator of adult neurogenesis, and has more recently been functionally linked to the aging circulatory systemic environment. In this review we examine the role of the aging systemic environment in regulating adult neurogenesis and cognitive function. We discuss recent work from our group using the aging model of heterochronic parabiosis - in which the circulatory system of two animals is connected - to highlight the contribution of circulatory immune factors to age-related impairments in adult neurogenesis and associated cognitive processes. Finally, we propose the possibility of combating brain aging by tapping into the 'rejuvenating' potential inherent in a young circulatory systemic environment.

    View details for DOI 10.1016/j.autrev.2012.10.014

    View details for PubMedID 23201925

  • Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival JOURNAL OF EXPERIMENTAL MEDICINE Luo, J., Elwood, F., Britschgi, M., Villeda, S., Zhang, H., Ding, Z., Zhu, L., Alabsi, H., Getachew, R., Narasimhan, R., Wabl, R., Fainberg, N., James, M. L., Wong, G., Relton, J., Gambhir, S. S., Pollard, J. W., Wyss-Coray, T. 2013; 210 (1): 157-172


    Colony-stimulating factor 1 (CSF1) and interleukin-34 (IL-34) are functional ligands of the CSF1 receptor (CSF1R) and thus are key regulators of the monocyte/macrophage lineage. We discovered that systemic administration of human recombinant CSF1 ameliorates memory deficits in a transgenic mouse model of Alzheimer's disease. CSF1 and IL-34 strongly reduced excitotoxin-induced neuronal cell loss and gliosis in wild-type mice when administered systemically before or up to 6 h after injury. These effects were accompanied by maintenance of cAMP responsive element-binding protein (CREB) signaling in neurons rather than in microglia. Using lineage-tracing experiments, we discovered that a small number of neurons in the hippocampus and cortex express CSF1R under physiological conditions and that kainic acid-induced excitotoxic injury results in a profound increase in neuronal receptor expression. Selective deletion of CSF1R in forebrain neurons in mice exacerbated excitotoxin-induced death and neurodegeneration. We conclude that CSF1 and IL-34 provide powerful neuroprotective and survival signals in brain injury and neurodegeneration involving CSF1R expression on neurons.

    View details for DOI 10.1084/jem.20120412

    View details for Web of Science ID 000313560900014

    View details for PubMedID 23296467

    View details for PubMedCentralID PMC3549715

  • Changes of the Enteric Nervous System in Amyloid-beta Protein Precursor Transgenic Mice Correlate with Disease Progression JOURNAL OF ALZHEIMERS DISEASE Semar, S., Klotz, M., Letiembre, M., Van Ginneken, C., Braun, A., Jost, V., Bischof, M., Lammers, W. J., Liu, Y., Fassbender, K., Wyss-Coray, T., Kirchhoff, F., Schaefer, K. 2013; 36 (1): 7-20


    In Alzheimer's disease (AD), fatal neuronal cell loss occurs long before relevant evidence can lead to a reliable diagnosis. If characteristic pathological alterations take place in the enteric nervous system (ENS), it could be one of the most promising targets for an early diagnosis, using submucosal biopsies from the gut. We therefore investigated time- and spatial-dependent changes in an amyloid-β protein precursor (AβPP) overexpressing transgenic mouse model to examine early changes within the ENS. Wholemount preparations and paraffin sections were analyzed for the expression of neuronal, glial, and innate immunity markers. Isolated myenteric networks were screened for differences in overall protein expression, and a motility analysis delivered functional data. The level of AβPP in the gut was significantly higher in the AD mouse model than in wild-type mice and also higher in the gut than in the brain at all ages investigated. The transcriptional level of Nestin, GFAP, and TLR4 increased with age with a peak at 3 months. At the protein level, human amyloid-β was located in myenteric neurons. Myenteric networks showed a reduction of the neuronal density in AβPP compared to wild-type mice, which was functionally relevant as revealed by motility analysis. The ENS undergoes significant changes during the early onset of AβPP expression in AD mouse models that appear before those seen in the brain as demonstrated in this study. Thus, there is a chance of determining similar alterations in the human gut of AD patients, which could be used to develop early diagnostic approaches.

    View details for DOI 10.3233/JAD-120511

    View details for Web of Science ID 000320030200002

    View details for PubMedID 23531500

  • The role of inflammation in age-related disease AGING-US Howcroft, T. K., Campisi, J., Louis, G. B., Smith, M. T., Wise, B., Wyss-Coray, T., Augustine, A. D., McElhaney, J. E., Kohanski, R., Sierra, F. 2013; 5 (1): 84-93


    The National Institutes of Health (NIH) Geroscience Interest Group (GSIG) sponsored workshop, The Role of Inflammation inAge-Related Disease, was held September 6th-7th, 2012 in Bethesda, MD. It is now recognized that a mild pro-inflammatory state is correlated with the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan. Four sessions explored the intrinsic, environmental exposures and immune pathways by which chronic inflammation are generated, sustained, and lead to age-associated diseases. At the conclusion of the workshop recommendations to accelerate progress toward understanding the mechanistic bases of chronic disease were identified.

    View details for Web of Science ID 000315982300007

    View details for PubMedID 23474627

  • beta 2-microglobulin regulates the age-related decline in adult neurogenesis and cognitive function 11th International Congress of Neuroimmunology (ISNI) Villeda, S., Park, J., He, Y., Wabl, R., Bieri, G., Luo, J., Grant, J., Wyss-Coray, T. ELSEVIER SCIENCE BV. 2012: 159–60
  • Changes in beclin 1 associated with Alzheimer's disease negatively regulate retromer and impair phagocytosis of amyloid-beta 11th International Congress of Neuroimmunology (ISNI) Lucin, K., O'Brien, C., Bieri, G., Czirr, E., Mosher, K., Mastroeni, D., Rogers, J., Spencer, B., Masliah, E., Wyss-Coray, T. ELSEVIER SCIENCE BV. 2012: 104–
  • Neural progenitor cells regulate microglia functions and activity NATURE NEUROSCIENCE Mosher, K. I., Andres, R. H., Fukuhara, T., Bieri, G., Hasegawa-Moriyama, M., He, Y., Guzman, R., Wyss-Coray, T. 2012; 15 (11): 1485-1487


    We found mouse neural progenitor cells (NPCs) to have a secretory protein profile distinct from other brain cells and to modulate microglial activation, proliferation and phagocytosis. NPC-derived vascular endothelial growth factor was necessary and sufficient to exert at least some of these effects in mice. Thus, neural precursor cells may not only be shaped by microglia, but also regulate microglia functions and activity.

    View details for DOI 10.1038/nn.3233

    View details for Web of Science ID 000310424900007

    View details for PubMedID 23086334

    View details for PubMedCentralID PMC3495979

  • Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice JOURNAL OF NEUROINFLAMMATION Britschgi, M., Takeda-Uchimura, Y., Rockenstein, E., Johns, H., Masliah, E., Wyss-Coray, T. 2012; 9


    The neuronal microtubule-associated protein tau becomes hyperphosphorylated and forms aggregates in tauopathies but the processes leading to this pathological hallmark are not understood. Because tauopathies are accompanied by neuroinflammation and the complement cascade forms a key innate immune pathway, we asked whether the complement system has a role in the development of tau pathology.We tested this hypothesis in two mouse models, which expressed either a central inhibitor of complement or lacked an inhibitor of the terminal complement pathway. Complement receptor-related gene/protein y is the natural inhibitor of the central complement component C3 in rodents. Expressing a soluble variant (sCrry) reduced the number of phospho-tau (AT8 epitope) positive neurons in the brain stem, cerebellum, cortex, and hippocampus of aged P301L mutant tau/sCrry double-transgenic mice compared with tau single-transgenic littermates (JNPL3 line). CD59a is the major inhibitor of formation of the membrane attack complex in mice. Intrahippocampal injection of adeno-associated virus encoding mutant human P301L tau into Cd59a-/- mice resulted in increased numbers of AT8-positive cells compared with wild-type controls. This was accompanied by neuronal and synaptic loss and reduced dendritic integrity.Our data in two independent mouse models with genetic changes in key regulators of the complement system support the hypothesis that the terminal pathway has an active role in the development of tau pathology. We propose that inhibition of the terminal pathway may be beneficial in tauopathies.

    View details for DOI 10.1186/1742-2094-9-220

    View details for Web of Science ID 000311733500001

    View details for PubMedID 22989354

  • The 1st International standard for transforming growth factor-beta 3 (TGF-beta 3) JOURNAL OF IMMUNOLOGICAL METHODS Wadhwa, M., Dilger, P., Hamill, M., Bending, D., Gibbs, S., Wu, G., Read, J., Wyss-Coray, T., Zhang, H., Little, J., Getliffe, K. M., Kai, G., Wang, W., Bender, D., Bird, C., Heath, A. B., Cooke, A., Thorpe, R. 2012; 380 (1-2): 1-9


    One candidate preparation of human sequence recombinant transforming growth factor-β3 (TGF-β3) was formulated and lyophilized at NIBSC prior to evaluation in a collaborative study for its suitability to serve as an international standard. The preparation was tested by 8 laboratories using in vitro bioassays and immunoassays. The candidate preparation 09/234 was judged suitable to serve as an international standard based on the data obtained for biological activity and stability. On the basis of the results reported here, the preparation coded 09/234 was established by the WHO Expert Committee on Biological Standardisation (ECBS) as the WHO 1st IS for human TGF-β3 with an assigned value for TGF-β3 activity of 19,000 IU/ampoule.

    View details for DOI 10.1016/j.jim.2012.03.002

    View details for Web of Science ID 000305362300001

    View details for PubMedID 22464938

  • Heparan Sulfate Subdomains that are Degraded by Sulf Accumulate in Cerebral Amyloid beta Plaques of Alzheimer's Disease Evidence from Mouse Models and Patients AMERICAN JOURNAL OF PATHOLOGY Hosono-Fukao, T., Ohtake-Niimi, S., Hoshino, H., Britschgi, M., Akatsu, H., Hossain, M. M., Nishitsuji, K., van Kuppevelt, T. H., Kimata, K., Michikawa, M., Wyss-Coray, T., Uchimura, K. 2012; 180 (5): 2056-2067


    Alzheimer's disease (AD) is characterized by extracellular cerebral accumulation of amyloid β peptide (Aβ). Heparan sulfate (HS) is a glycosaminoglycan that is abundant in the extracellular space. The state of sulfation within the HS chain influences its ability to interact with a variety of proteins. Highly sulfated domains within HS are crucial for Aβ aggregation in vitro. Here, we investigated the expression of the sulfated domains and HS disaccharide composition in the brains of Tg2576, J20, and T41 transgenic AD mouse models, and patients with AD. RB4CD12, a phage display antibody, recognizes highly sulfated domains of HS. The RB4CD12 epitope is abundant in the basement membrane of brain vessels under physiological conditions. In the cortex and hippocampus of the mice and patients with AD, RB4CD12 strongly stained both diffuse and neuritic amyloid plaques. Interestingly, RB4CD12 also stained the intracellular granules of certain hippocampal neurons in AD brains. Disaccharide compositions in vessel-enriched and nonvasculature fractions of Tg2576 mice and AD patients were found to be comparable to those of non-transgenic and non-demented controls, respectively. The RB4CD12 epitope in amyloid plaques was substantially degraded ex vivo by Sulf-1 and Sulf-2, extracellular HS endosulfatases. These results indicate that formation of highly sulfated HS domains may be upregulated in conjunction with AD pathogenesis, and that these domains can be enzymatically remodeled in AD brains.

    View details for DOI 10.1016/j.ajpath.2012.01.015

    View details for Web of Science ID 000303641000029

    View details for PubMedID 22429964

  • The immunology of neurodegeneration JOURNAL OF CLINICAL INVESTIGATION Czirr, E., Wyss-Coray, T. 2012; 122 (4): 1156-1163


    While immune responses in neurodegeneration were regarded as little more than a curiosity a decade ago, they are now increasingly moving toward center stage. Factors driving this movement include the recognition that most of the relevant immune molecules are produced within the brain, that microglia are proficient immune cells shaping neuronal circuitry and fate, and that systemic immune responses affect brain function. We will review this complex field from the perspective of neurons, extra-neuronal brain cells, and the systemic environment and highlight the possibility that cell intrinsic innate immune molecules in neurons may function in neurodegenerative processes.

    View details for DOI 10.1172/JCI58656

    View details for Web of Science ID 000302281800007

    View details for PubMedID 22466657

  • Thy1-hAPP(Lond/Swe+) mouse model of Alzheimer's disease displays broad behavioral deficits in sensorimotor, cognitive and social function. Brain and behavior Faizi, M., Bader, P. L., Saw, N., Nguyen, T. V., Beraki, S., Wyss-Coray, T., Longo, F. M., Shamloo, M. 2012; 2 (2): 142-154


    Alzheimer's disease (AD), the most common form of dementia, is an age-dependent progressive neurodegenerative disorder. β-amyloid, a metabolic product of the amyloid precursor protein (APP), plays an important role in the pathogenesis of AD. The Thy1-hAPP(Lond/Swe+) (line 41) transgenic mouse overexpresses human APP751 and contains the London (V717I) and Swedish (K670M/N671L) mutations. Here, we used a battery of behavioral tests to evaluate general activity, cognition, and social behavior in six-month-old male Thy1-hAPP(Lond/Swe+) mice. We found hyperactivity in a novel environment as well as significant deficits in spontaneous alternation behavior. In fear conditioning (FC), Thy1-hAPP(Lond/Swe+) mice did not display deficits in acquisition or in memory retrieval in novel context of tone-cued FC, but they showed significant memory retrieval impairment during contextual testing in an identical environment. Surprisingly, in a standard hidden platform water maze, no significant deficit was detected in mutant mice. However, a delayed-matching-to-place paradigm revealed a significant deficit in Thy1-hAPP(Lond/Swe+) mice. Lastly, in the social novelty session of a three-chamber test, Thy1-hAPP(Lond/Swe+) mice exhibited a significantly decreased interest in a novel versus a familiar stranger compared to control mice. This could possibly be explained by decreased social memory or discrimination and may parallel disturbances in social functioning in human AD patients. In conclusion, the Thy1-hAPP(Lond/Swe+) mouse model of AD displayed a behavioral phenotype that resembles, in part, the cognitive and psychiatric symptoms experienced in AD patients.

    View details for DOI 10.1002/brb3.41

    View details for PubMedID 22574282

  • Thy1-hAPP(Lond/Swe+) mouse model of Alzheimer's disease displays broad behavioral deficits in sensorimotor, cognitive and social function BRAIN AND BEHAVIOR Faizi, M., Bader, P. L., Saw, N., Nguyen, T. V., Beraki, S., Wyss-Coray, T., Longo, F. M., Shamloo, M. 2012; 2 (2): 142-154


    Alzheimer's disease (AD), the most common form of dementia, is an age-dependent progressive neurodegenerative disorder. β-amyloid, a metabolic product of the amyloid precursor protein (APP), plays an important role in the pathogenesis of AD. The Thy1-hAPP(Lond/Swe+) (line 41) transgenic mouse overexpresses human APP751 and contains the London (V717I) and Swedish (K670M/N671L) mutations. Here, we used a battery of behavioral tests to evaluate general activity, cognition, and social behavior in six-month-old male Thy1-hAPP(Lond/Swe+) mice. We found hyperactivity in a novel environment as well as significant deficits in spontaneous alternation behavior. In fear conditioning (FC), Thy1-hAPP(Lond/Swe+) mice did not display deficits in acquisition or in memory retrieval in novel context of tone-cued FC, but they showed significant memory retrieval impairment during contextual testing in an identical environment. Surprisingly, in a standard hidden platform water maze, no significant deficit was detected in mutant mice. However, a delayed-matching-to-place paradigm revealed a significant deficit in Thy1-hAPP(Lond/Swe+) mice. Lastly, in the social novelty session of a three-chamber test, Thy1-hAPP(Lond/Swe+) mice exhibited a significantly decreased interest in a novel versus a familiar stranger compared to control mice. This could possibly be explained by decreased social memory or discrimination and may parallel disturbances in social functioning in human AD patients. In conclusion, the Thy1-hAPP(Lond/Swe+) mouse model of AD displayed a behavioral phenotype that resembles, in part, the cognitive and psychiatric symptoms experienced in AD patients.

    View details for DOI 10.1002/brb3.41

    View details for Web of Science ID 000209173900005

    View details for PubMedCentralID PMC3345358

  • Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model NEUROBIOLOGY OF AGING Lifshitz, V., Weiss, R., Benromano, T., Kfir, E., Blumenfeld-Katzir, T., Tempel-Brami, C., Assaf, Y., Xia, W., Wyss-Coray, T., Weiner, H. L., Frenkel, D. 2012; 33 (2)


    Cerebrovascular amyloidosis is caused by amyloid accumulation in walls of blood vessel walls leading to hemorrhagic stroke and cognitive impairment. Transforming growth factor-β1 (TGF-β1) expression levels correlate with the degree of cerebrovascular amyloid deposition in Alzheimer's disease (AD) and TGF-β1 immunoreactivity in such cases is increased along the cerebral blood vessels. Here we show that a nasally administered proteosome-based adjuvant activates macrophages and decreases vascular amyloid in TGF-β1 mice. Animals were nasally treated with a proteosome-based adjuvant on a weekly basis for 3 months beginning at age 13 months. Using magnetic resonance imaging (MRI) we found that while control animals showed a significant cerebrovascular pathology, proteosome-based adjuvant prevents further brain damage and prevents pathological changes in the blood-brain barrier. Using an object recognition test and Y-maze, we found significant improvement in cognition in the treated group. Our findings support the potential use of a macrophage immunomodulator as a novel approach to reduce cerebrovascular amyloid, prevent microhemorrhage, and improve cognition.

    View details for DOI 10.1016/j.neurobiolaging.2011.01.006

    View details for Web of Science ID 000298171800051

    View details for PubMedID 21371785

  • Inflammation in Alzheimer Disease-A Brief Review of the Basic Science and Clinical Literature COLD SPRING HARBOR PERSPECTIVES IN MEDICINE Wyss-Coray, T., Rogers, J. 2012; 2 (1)


    Biochemical and neuropathological studies of brains from individuals with Alzheimer disease (AD) provide clear evidence for an activation of inflammatory pathways, and long-term use of anti-inflammatory drugs is linked with reduced risk to develop the disease. As cause and effect relationships between inflammation and AD are being worked out, there is a realization that some components of this complex molecular and cellular machinery are most likely promoting pathological processes leading to AD, whereas other components serve to do the opposite. The challenge will be to find ways of fine tuning inflammation to delay, prevent, or treat AD.

    View details for DOI 10.1101/cshperspect.a006346

    View details for Web of Science ID 000314239200010

    View details for PubMedID 22315714

    View details for PubMedCentralID PMC3253025

  • Identification of a central role for complement in osteoarthritis NATURE MEDICINE Wang, Q., Rozelle, A. L., Lepus, C. M., Scanzello, C. R., Song, J. J., Larsen, D. M., Crish, J. F., Bebek, G., Ritter, S. Y., Lindstrom, T. M., Hwang, I., Wong, H. H., Punzi, L., Encarnacion, A., Shamloo, M., Goodman, S. B., Wyss-Coray, T., Goldring, S. R., Banda, N. K., Thurman, J. M., Gobezie, R., Crow, M. K., Holers, V. M., Lee, D. M., Robinson, W. H. 2011; 17 (12): 1674-U196


    Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.

    View details for DOI 10.1038/nm.2543

    View details for Web of Science ID 000297978000042

    View details for PubMedID 22057346

    View details for PubMedCentralID PMC3257059

  • Modeling of Pathological Traits in Alzheimer's Disease Based on Systemic Extracellular Signaling Proteome MOLECULAR & CELLULAR PROTEOMICS Britschgi, M., Rufibach, K., Huang, S. L., Clark, C. M., Kaye, J. A., Li, G., Peskind, E. R., Quinn, J. F., Galasko, D. R., Wyss-Coray, T. 2011; 10 (10)


    The study of chronic brain diseases including Alzheimer's disease in patients is typically limited to brain imaging or psychometric testing. Given the epidemic rise and insufficient knowledge about pathological pathways in sporadic Alzheimer's disease, new tools are required to identify the molecular changes underlying this disease. We hypothesize that levels of specific secreted cellular signaling proteins in cerebrospinal fluid or plasma correlate with pathological changes in the Alzheimer's disease brain and can thus be used to discover signaling pathways altered in the disease. Here we measured 91 proteins of this subset of the cellular communication proteome in plasma or cerebrospinal fluid in patients with Alzheimer's disease and cognitively normal controls to mathematically model disease-specific molecular traits. We found small numbers of signaling proteins that were able to model key pathological markers of Alzheimer's disease, including levels of cerebrospinal fluid β-amyloid and tau, and classify disease in independent samples. Several of these factors had previously been implicated in Alzheimer's disease supporting the validity of our approach. Our study also points to proteins which were previously unknown to be associated with Alzheimer's disease thereby implicating novel signaling pathways in this disorder.

    View details for DOI 10.1074/mcp.M111.008862

    View details for Web of Science ID 000295773800019

    View details for PubMedID 21742799

    View details for PubMedCentralID PMC3205866

  • The ageing systemic milieu negatively regulates neurogenesis and cognitive function NATURE Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., Stan, T. M., Fainberg, N., Ding, Z., Eggel, A., Lucin, K. M., Czirr, E., Park, J., Couillard-Despres, S., Aigner, L., Li, G., Peskind, E. R., Kaye, J. A., Quinn, J. F., Galasko, D. R., Xie, X. S., Rando, T. A., Wyss-Coray, T. 2011; 477 (7362): 90-U157


    In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.

    View details for DOI 10.1038/nature10357

    View details for Web of Science ID 000294404300037

    View details for PubMedID 21886162

    View details for PubMedCentralID PMC3170097

  • Complement Receptor 2 Is Expressed in Neural Progenitor Cells and Regulates Adult Hippocampal Neurogenesis JOURNAL OF NEUROSCIENCE Moriyama, M., Fukuhara, T., Britschgi, M., He, Y., Narasimhan, R., Villeda, S., Molina, H., Huber, B. T., Holers, M., Wyss-Coray, T. 2011; 31 (11): 3981-3989


    Injury and inflammation are potent regulators of adult neurogenesis. As the complement system forms a key immune pathway that may also exert critical functions in neural development and neurodegeneration, we asked whether complement receptors regulate neurogenesis. We discovered that complement receptor 2 (CR2), classically known as a coreceptor of the B-lymphocyte antigen receptor, is expressed in adult neural progenitor cells (NPCs) of the dentate gyrus. Two of its ligands, C3d and interferon-α (IFN-α), inhibited proliferation of wild-type NPCs but not NPCs derived from mice lacking Cr2 (Cr2(-/-)), indicating functional Cr2 expression. Young and old Cr2(-/-) mice exhibited prominent increases in basal neurogenesis compared with wild-type littermates, whereas intracerebral injection of C3d resulted in fewer proliferating neuroblasts in wild-type than in Cr2(-/-) mice. We conclude that Cr2 regulates hippocampal neurogenesis and propose that increased C3d and IFN-α production associated with brain injury or viral infections may inhibit neurogenesis.

    View details for DOI 10.1523/JNEUROSCI.3617-10.2011

    View details for Web of Science ID 000288455700008

    View details for PubMedID 21411641

  • Workshop Summary: Roles of the TNF Family in Neuronal Development, Function and Pathology 12th Biennial International Tumor Necrosis Factor Conference Tansey, M. G., Wyss-Coray, T. SPRINGER-VERLAG BERLIN. 2011: 537–538

    View details for DOI 10.1007/978-1-4419-6612-4_55

    View details for Web of Science ID 000291501300057

    View details for PubMedID 21153358

  • Beclin 1 Complex in Autophagy and Alzheimer Disease ARCHIVES OF NEUROLOGY Jaeger, P. A., Wyss-Coray, T. 2010; 67 (10): 1181-1184


    Beclin 1 is a protein involved in the regulation of autophagy and has been shown to be reduced in patients with Alzheimer disease. This review summarizes the current research data that link disturbances in autophagy, a cellular degradation and maintenance pathway, to the development of Alzheimer disease and related neurodegenerative diseases. It also provides a brief overview of the existing pharmacological interventions available to modulate autophagy activity in mammalian cells.

    View details for Web of Science ID 000282766300003

    View details for PubMedID 20937944

  • Cellular Source of Apolipoprotein E4 Determines Neuronal Susceptibility to Excitotoxic Injury in Transgenic Mice AMERICAN JOURNAL OF PATHOLOGY Buttini, M., Masliah, E., Yu, G., Palop, J. J., Chang, S., Bernardo, A., Lin, C., Wyss-Coray, T., Huang, Y., Mucke, L. 2010; 177 (2): 563-569


    The lipid transport protein apolipoprotein E (apoE) is abundantly expressed in the brain. Its main isoforms in humans are apoE2, apoE3, and apoE4. ApoE4 is the major known genetic risk factor for Alzheimer's disease and also contributes to the pathogenesis of various other neurological conditions. In the central nervous system, apoE is synthesized by glial cells and neurons, but it is unclear whether the cellular source affects its biological activities. To address this issue, we induced excitotoxic injury by systemic kainic acid injection in transgenic Apoe knockout mice expressing human apoE isoforms in astrocytes or neurons. Regardless of its cellular source, apoE3 expression protected neuronal synapses and dendrites against the excitotoxicity seen in apoE-deficient mice. Astrocyte-derived apoE4, which has previously been shown to have detrimental effects in vitro, was as excitoprotective as apoE3 in vivo. In contrast, neuronal expression of apoE4 was not protective and resulted in loss of cortical neurons after excitotoxic challenge, indicating that neuronal apoE4 promotes excitotoxic cell death. Thus, an imbalance between astrocytic (excitoprotective) and neuronal (neurotoxic) apoE4 expression may increase susceptibility to diverse neurological diseases involving excitotoxic mechanisms.

    View details for DOI 10.2353/ajpath.2010.090973

    View details for Web of Science ID 000280894600008

    View details for PubMedID 20595630

  • Angiotensin II sustains brain inflammation in mice via TGF-beta JOURNAL OF CLINICAL INVESTIGATION Lanz, T. V., Ding, Z., Ho, P. P., Luo, J., Agrawal, A. N., Srinagesh, H., Axtell, R., Zhang, H., Platten, M., Wyss-Coray, T., Steinman, L. 2010; 120 (8): 2782-2794


    The renin-angiotensin-aldosterone system (RAAS) is a key hormonal system regulating blood pressure. However, expression of RAAS components has recently been detected in immune cells, and the RAAS has been implicated in several mouse models of autoimmune disease. Here, we have identified Ang II as a paracrine mediator, sustaining inflammation in the CNS in the EAE mouse model of MS via TGF-beta. Ang II type 1 receptors (AT1Rs) were found to be primarily expressed in CNS-resident cells during EAE. In vitro, astrocytes and microglia responded to Ang II treatment by inducing TGF-beta expression via a pathway involving the TGF-beta-activating protease thrombospondin-1 (TSP-1). TGF-beta upregulation in astrocytes and microglia during EAE was blocked with candesartan (CA), an inhibitor of AT1R. Treatment of EAE with CA ameliorated paralysis and blunted lymphocyte infiltration into the CNS, outcomes that were also seen with genetic ablation of AT1Ra and treatment with an inhibitor of TSP-1. These data suggest that AT1R antagonists, frequently prescribed as antihypertensives, may be useful to interrupt this proinflammatory, CNS-specific pathway in individuals with MS.

    View details for DOI 10.1172/JCI41709

    View details for Web of Science ID 000280492100015

    View details for PubMedID 20628203

    View details for PubMedCentralID PMC2912186

  • Regulation of Amyloid Precursor Protein Processing by the Beclin 1 Complex PLOS ONE Jaeger, P. A., Pickford, F., Sun, C., Lucin, K. M., Masliah, E., Wyss-Coray, T. 2010; 5 (6)


    Autophagy is an intracellular degradation pathway that functions in protein and organelle turnover in response to starvation and cellular stress. Autophagy is initiated by the formation of a complex containing Beclin 1 (BECN1) and its binding partner Phosphoinositide-3-kinase, class 3 (PIK3C3). Recently, BECN1 deficiency was shown to enhance the pathology of a mouse model of Alzheimer Disease (AD). However, the mechanism by which BECN1 or autophagy mediate these effects are unknown. Here, we report that the levels of Amyloid precursor protein (APP) and its metabolites can be reduced through autophagy activation, indicating that they are a substrate for autophagy. Furthermore, we find that knockdown of Becn1 in cell culture increases the levels of APP and its metabolites. Accumulation of APP and APP C-terminal fragments (APP-CTF) are accompanied by impaired autophagosomal clearance. Pharmacological inhibition of autophagosomal-lysosomal degradation causes a comparable accumulation of APP and APP-metabolites in autophagosomes. Becn1 reduction in cell culture leads to lower levels of its binding partner Pik3c3 and increased presence of Microtubule-associated protein 1, light chain 3 (LC3). Overexpression of Becn1, on the other hand, reduces cellular APP levels. In line with these observations, we detected less BECN1 and PIK3C3 but more LC3 protein in brains of AD patients. We conclude that BECN1 regulates APP processing and turnover. BECN1 is involved in autophagy initiation and autophagosome clearance. Accordingly, BECN1 deficiency disrupts cellular autophagy and autophagosomal-lysosomal degradation and alters APP metabolism. Together, our findings suggest that autophagy and the BECN1-PIK3C3 complex regulate APP processing and play an important role in AD pathology.

    View details for DOI 10.1371/journal.pone.0011102

    View details for Web of Science ID 000278775900004

    View details for PubMedID 20559548

  • Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in alpha-Synuclein Models of Parkinson's and Lewy Body Diseases JOURNAL OF NEUROSCIENCE Spencer, B., Potkar, R., Trejo, M., Rockenstein, E., Patrick, C., Gindi, R., Adame, A., Wyss-Coray, T., Masliah, E. 2009; 29 (43): 13578-13588


    Accumulation of the synaptic protein alpha-synuclein (alpha-syn) is a hallmark of Parkinson's disease (PD) and Lewy body disease (LBD), a heterogeneous group of disorders with dementia and parkinsonism, where Alzheimer's disease and PD interact. Accumulation of alpha-syn in these patients might be associated with alterations in the autophagy pathway. Therefore, we postulate that delivery of beclin 1, a regulator of the autophagy pathway, might constitute a strategy toward developing a therapy for LBD/PD. Overexpression of alpha-syn from lentivirus transduction in a neuronal cell line resulted in lysosomal accumulation and alterations in autophagy. Coexpression of beclin 1 activated autophagy, reduced accumulation of alpha-syn, and ameliorated associated neuritic alterations. The effects of beclin 1 overexpression on LC3 and alpha-syn accumulation were partially blocked by 3-MA and completely blocked by bafilomycin A1. In contrast, rapamycin enhanced the effects of beclin 1. To evaluate the potential effects of activating autophagy in vivo, a lentivirus expressing beclin 1 was delivered to the brain of a alpha-syn transgenic mouse. Neuropathological analysis demonstrated that beclin 1 injections ameliorated the synaptic and dendritic pathology in the tg mice and reduced the accumulation of alpha-syn in the limbic system without any significant deleterious effects. This was accompanied by enhanced lysosomal activation and reduced alterations in the autophagy pathway. Thus, beclin 1 plays an important role in the intracellular degradation of alpha-syn either directly or indirectly through the autophagy pathway and may present a novel therapeutic target for LBD/PD.

    View details for DOI 10.1523/JNEUROSCI.4390-09.2009

    View details for Web of Science ID 000271266600017

    View details for PubMedID 19864570

  • Immune Activation in Brain Aging and Neurodegeneration: Too Much or Too Little? NEURON Lucin, K. M., Wyss-Coray, T. 2009; 64 (1): 110-122


    Until recently, the brain was studied almost exclusively by neuroscientists and the immune system by immunologists, fuelling the notion that these systems represented two isolated entities. However, as more data suggest an important role of the immune system in regulating the progression of brain aging and neurodegenerative disease, it has become clear that the crosstalk between these systems can no longer be ignored and a new interdisciplinary approach is necessary. A central question that emerges is whether immune and inflammatory pathways become hyperactivated with age and promote degeneration or whether insufficient immune responses, which fail to cope with age-related stress, may contribute to disease. We try to explore here the consequences of gain versus loss of function with an emphasis on microglia as sensors and effectors of immune function in the brain, and we discuss the potential role of the peripheral environment in neurodegenerative diseases.

    View details for DOI 10.1016/j.neuron.2009.08.039

    View details for Web of Science ID 000271454400015

    View details for PubMedID 19840553

  • The p75 Neurotrophin Receptor Promotes Amyloid-beta(1-42)-Induced Neuritic Dystrophy In Vitro and In Vivo JOURNAL OF NEUROSCIENCE Knowles, J. K., Rajadas, J., Nguyen, T. V., Yang, T., LeMieux, M. C., Griend, L. V., Ishikawa, C., Massa, S. M., Wyss-Coray, T., Longo, F. M. 2009; 29 (34): 10627-10637


    Oligomeric forms of amyloid-beta (Abeta) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75(NTR)) has been implicated in Abeta-induced neurodegeneration. To further define the functions of p75(NTR) in AD, we examined the interaction of oligomeric Abeta(1-42) with p75(NTR), and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Abeta, and fluorescence resonance energy transfer analysis revealed that Abeta oligomers interact with the extracellular domain of p75(NTR). In vitro studies of Abeta-induced death in neuron cultures isolated from wild-type and p75(NTR-/-) mice, in which the p75(NTR) extracellular domain is deleted, showed reduced sensitivity of mutant cells to Abeta-induced cell death. Interestingly, Abeta-induced neuritic dystrophy and activation of c-Jun, a known mediator of Abeta-induced deleterious signaling, were completely prevented in p75(NTR-/-) neuron cultures. Thy1-hAPP(Lond/Swe) x p75(NTR-/-) mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild-type p75(NTR). Abeta levels were not affected, suggesting that removal of p75(NTR) extracellular domain reduced the ability of excess Abeta to promote neuritic degeneration. These findings indicate that although p75(NTR) likely does not mediate all Abeta effects, it does play a significant role in enabling Abeta-induced neurodegeneration in vitro and in vivo, establishing p75(NTR) as an important therapeutic target for AD.

    View details for DOI 10.1523/JNEUROSCI.0620-09.2009

    View details for Web of Science ID 000269317900017

    View details for PubMedID 19710315

    View details for PubMedCentralID PMC2771439

  • Bioactive TGF-beta can associate with lipoproteins and is enriched in those containing apolipoprotein E3 JOURNAL OF NEUROCHEMISTRY Tesseur, I., Zhang, H., Brecht, W., Corn, J., Gong, J., Yanagisawa, K., Michikawa, M., Weisgraber, K., Huang, Y., Wyss-Coray, T. 2009; 110 (4): 1254-1262


    Transforming growth factor-beta1 (TGF-beta1) has central functions in development, tissue maintenance, and repair and has been implicated in major diseases. We discovered that TGF-beta1 contains several amphipathic helices and hydrophobic domains similar to apolipoprotein E (apoE), a protein involved in lipoprotein metabolism. Indeed, TGF-beta1 associates with lipoproteins isolated from human plasma, cultured liver cells, or astrocytes, and its bioactivity was highest in high-density lipoprotein preparations. Importantly, lipoproteins containing the apoE3 isoform had higher TGF-beta levels and bioactivity than those containing apoE4, a major genetic risk factor for atherosclerosis and Alzheimer's disease. Because TGF-beta1 can be protective in these diseases an association with apoE3 may be beneficial. Association of TGF-beta with different types of lipoproteins may facilitate its diffusion, regulate signaling, and offer additional specificity for this important growth factor.

    View details for DOI 10.1111/j.1471-4159.2009.06222.x

    View details for Web of Science ID 000268221500011

    View details for PubMedID 19549280

  • Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Britschgi, M., Olin, C. E., Johns, H. T., Takeda-Uchimura, Y., LeMieux, M. C., Rufibach, K., Rajadas, J., Zhang, H., Tomooka, B., Robinson, W. H., Clark, C. M., Fagan, A. M., Galasko, D. R., Holtzman, D. M., Jutel, M., Kaye, J. A., Lemere, C. A., Leszek, J., Li, G., Peskind, E. R., Quinn, J. F., Yesavage, J. A., Ghiso, J. A., Wyss-Coray, T. 2009; 106 (29): 12145-12150


    A number of distinct beta-amyloid (Abeta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Abeta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.

    View details for DOI 10.1073/pnas.0904866106

    View details for Web of Science ID 000268178400059

    View details for PubMedID 19581601

  • Blood Protein Signature for the Early Diagnosis of Alzheimer Disease ARCHIVES OF NEUROLOGY Britschgi, M., Wyss-Coray, T. 2009; 66 (2): 161-165


    Alzheimer disease (AD) has become one of the main health concerns for the elderly population in the United States. Current treatments target symptoms only, but several advanced clinical trials are testing new drugs that are potentially disease modifying. Because AD is still difficult to diagnose in its earliest stages and the disease process is estimated to start many years before current clinical diagnosis is made, accurate and simple diagnostic tools are urgently needed. We recently described a blood-based panel of secreted signaling proteins that distinguishes between blinded samples from patients with AD and control subjects with high accuracy. The same proteins also predicted progression to AD in preclinical patients with mild cognitive impairment several years before clinical diagnosis for AD was made. Herein, we describe these findings and discuss the potential for a more general application of our proteomic approach in understanding and diagnosing disease.

    View details for Web of Science ID 000263203200003

    View details for PubMedID 19064741

  • Bioluminescence analysis of Smad-dependent TGF-beta signaling in live mice. Methods in molecular biology (Clifton, N.J.) Luo, J., Wyss-Coray, T. 2009; 574: 193-202


    TGF-beta signaling via the Smad2/3 pathway has key roles in development and tissue homeostasis. Perturbations of the TGF-beta signaling are involved in the pathogenesis of many human diseases, including cancer, fibrotic disorders, developmental defects, and neurodegeneration. To study the temporal and spatial patterns of Smad2/3-dependent signaling in living animals, we engineered transgenic mice with a Smad-responsive luciferase reporter (SBE-luc mice). Smad2/3-dependent signaling can be assessed non-invasively in living mice by bioluminescence imaging. To identify the cellular source of the bioluminescence signal, we generated new reporter mice expressing a trifusion protein containing luciferase, red fluorescent protein (RFP), and thymidine kinase under the control of the same SBE promoter (SBE-lucRT mice). SBE-luc and SBE-lucRT mice can be used to study temporal, tissue-specific activation of Smad2/3-dependent signaling in living mice as well as for the identification of endogenous or synthetic modulators of this pathway.

    View details for DOI 10.1007/978-1-60327-321-3_16

    View details for PubMedID 19685310

  • TGF beta signaling in immune mediated CNS disease Wyss-Coray, T., Ding, Z., Luo, J. ELSEVIER SCIENCE BV. 2008: 205–
  • Microglia - A wrench in the running wheel? NEURON Villeda, S., Wyss-Coray, T. 2008; 59 (4): 527-529


    Increasing the amount of physical activity has been observed to ameliorate the progression of Alzheimer's disease (AD), as well as enhance neurogenesis. Choi et al. in this issue of Neuron report that the expression of Presenilin 1 (PS1) variants, responsible for the early onset of familial AD, are capable of mitigating the regenerative effects associated with increased activity and environmental enrichment likely through changes in resident microglia and their secreted factors.

    View details for DOI 10.1016/j.neuron.2008.08.005

    View details for Web of Science ID 000258944900003

    View details for PubMedID 18760689

  • Genes contributing to prion pathogenesis JOURNAL OF GENERAL VIROLOGY Tamguney, G., Giles, K., Glidden, D. V., Lessard, P., Wille, H., Tremblay, P., Groth, D. F., Yehiely, F., Korth, C., Moore, R. C., Tatzelt, J., Rubinstein, E., Boucheix, C., Yang, X., Stanley, P., Lisanti, M. P., Dwek, R. A., Rudd, P. M., Moskovitz, J., Epstein, C. J., Cruz, T. D., Kuziel, W. A., Maeda, N., Sap, J., Ashe, K. H., Carlson, G. A., Tesseur, I., Wyss-Coray, T., Mucke, L., Weisgraber, K. H., Mahley, R. W., Cohen, F. E., Prusiner, S. B. 2008; 89: 1777-1788


    Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP(C)) to a misfolded, pathogenic isoform (PrP(Sc)). Prion inoculation experiments in mice expressing homologous PrP(C) molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes, because their products either colocalize with PrP, are associated with Alzheimer's disease, are elevated during prion disease, or function in PrP-mediated signalling, PrP glycosylation, or protein maintenance. Whereas some of the candidates tested may have a role in the normal function of PrP(C), our data show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1), and transgenic overexpression of human superoxide dismutase 1 (SOD1) prolonged incubation times by 13, 16 and 19 %, respectively.

    View details for DOI 10.1099/vir.0.2008/001255-0

    View details for Web of Science ID 000257554600026

    View details for PubMedID 18559949

  • The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice JOURNAL OF CLINICAL INVESTIGATION Pickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P. A., Small, S., Spencer, B., Rockenstein, E., Levine, B., Wyss-Coray, T. 2008; 118 (6): 2190-2199


    Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid beta (Abeta) accumulation, extracellular Abeta deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD.

    View details for DOI 10.1172/JCI33585

    View details for Web of Science ID 000256445100023

    View details for PubMedID 18497889

  • Bioluminescence in vivo imaging of autoimmune encephalomyelitis predicts disease JOURNAL OF NEUROINFLAMMATION Luo, J., Ho, P., Steinman, L., Wyss-Coray, T. 2008; 5


    Experimental autoimmune encephalomyelitis is a widely used animal model to understand not only multiple sclerosis but also basic principles of immunity. The disease is scored typically by observing signs of paralysis, which do not always correspond with pathological changes.Experimental autoimmune encephalomyelitis was induced in transgenic mice expressing an injury responsive luciferase reporter in astrocytes (GFAP-luc). Bioluminescence in the brain and spinal cord was measured non-invasively in living mice. Mice were sacrificed at different time points to evaluate clinical and pathological changes. The correlation between bioluminescence and clinical and pathological EAE was statistically analyzed by Pearson correlation analysis.Bioluminescence from the brain and spinal cord correlates strongly with severity of clinical disease and a number of pathological changes in the brain in EAE. Bioluminescence at early time points also predicts severity of disease.These results highlight the potential use of bioluminescence imaging to monitor neuroinflammation for rapid drug screening and immunological studies in EAE and suggest that similar approaches could be applied to other animal models of autoimmune and inflammatory disorders.

    View details for DOI 10.1186/1742-2094-5-6

    View details for Web of Science ID 000254547500001

    View details for PubMedID 18237444

  • Real-time Imaging of molecular signaling after stroke - Novel reporter mice for dissection of in vivo responses to TGF-beta 33rd International Stroke Conference Buckwalter, M. S., Luo, J., Debsi, B., Wyss-Coray, T. LIPPINCOTT WILLIAMS & WILKINS. 2008: 659–59
  • Bioluminescent imaging of excitotoxic and endotoxic brain injury in living mice 7th International Conference on Progress in Alzheimers and Parkinsons Disease Luo, J., Lin, A. H., Wyss-Coray, T. SPRINGER. 2008: 175–182
  • Glia-dependent TGF-beta signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis JOURNAL OF CLINICAL INVESTIGATION Luo, J., Ho, P. P., Buckwalter, M. S., Hsu, T., Lee, L. Y., Zhang, H., Kim, D., Kim, S., Gambhir, S. S., Steinman, L., Wyss-Coray, T. 2007; 117 (11): 3306-3315


    Autoimmune encephalomyelitis, a mouse model for multiple sclerosis, is characterized by the activation of immune cells, demyelination of axons in the CNS, and paralysis. We found that TGF-beta1 synthesis in glial cells and TGF-beta-induced signaling in the CNS were activated several days before the onset of paralysis in mice with autoimmune encephalomyelitis. While early production of TGF-beta1 was observed in glial cells TGF-beta signaling was activated in neurons and later in infiltrating T cells in inflammatory lesions. Systemic treatment with a pharmacological inhibitor of TGF-beta signaling ameliorated the paralytic disease and reduced the accumulation of pathogenic T cells and expression of IL-6 in the CNS. Priming of peripheral T cells was not altered, nor was the generation of TH17 cells, indicating that this effect was directed within the brain, yet affected the immune system. These results suggest that early production of TGF-beta1 in the CNS creates a permissive and dangerous environment for the initiation of autoimmune inflammation, providing a rare example of the brain modulating the immune system. Importantly, inhibition of TGF-beta signaling may have benefits in the treatment of the acute phase of autoimmune CNS inflammation.

    View details for DOI 10.1172/JCI31763

    View details for Web of Science ID 000250676000023

    View details for PubMedID 17965773

    View details for PubMedCentralID PMC2040317

  • Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins NATURE MEDICINE Ray, S., Britschgi, M., Herbert, C., Takeda-Uchimura, Y., Boxer, A., Blennow, K., Friedman, L. F., Galasko, D. R., Jutel, M., Karydas, A., Kaye, J. A., Leszek, J., Miller, B. L., Minthon, L., Quinn, J. F., Rabinovici, G. D., Robinson, W. H., Sabbagh, M. N., So, Y. T., Sparks, D. L., Tabaton, M., Tinklenberg, J., Yesavage, J. A., Tibshirani, R., Wyss-Coray, T. 2007; 13 (11): 1359-1362


    A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.

    View details for DOI 10.1038/nm1653

    View details for Web of Science ID 000250736900029

    View details for PubMedID 17934472

  • Orally administered TGF-beta is biologically active in the intestinal mucosa and enhances oral tolerance JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Ando, T., Hatsushika, K., Wako, M., Ohba, T., Koyama, K., Ohnuma, Y., Katoh, R., Ogawa, H., Okumura, K., Luo, J., Wyss-Coray, T., Nakao, A. 2007; 120 (4): 916-923


    Epidemiologic studies suggest that TGF-beta in breast milk provides protection against allergic disease during infancy. However, it is unclear whether orally administered TGF-beta, such as TGF-beta in human milk, retains and exerts its activity in the intestinal mucosa and can affect immune response (tolerance) to dietary antigens.We sought to determine whether orally administered TGF-beta is biologically active in intestinal mucosa and affects oral tolerance.Activity of orally administered TGF-beta in the intestinal mucosa was evaluated by means of in vivo imaging with transgenic mice expressing a Smad-responsive reporter construct (SBE-luc mice), by means of immunohistochemical staining with anti-phosphorylated Smad2 antibody, and by means of real-time RT-PCR analysis of TGF-beta and Smad7 mRNA expression. The effects of orally administered TGF-beta on oral tolerance induction were assessed in mice tolerized by means of high-dose ovalbumin (OVA) feeding.The oral administration of TGF-beta increased Smad-responsive reporter activity in the intestines of SBE-luc mice and induced Smad2 phosphorylation and TGF-beta and Smad7 mRNA expression in the intestines of BALB/c mice. Serum TGF-beta levels were also increased after oral administration of TGF-beta. BALB/c mice treated orally with OVA and TGF-beta showed augmented reduction of OVA-specific IgE and IgG1 antibodies, T-cell reactivity, and immediate-type skin reactions when compared with the mice treated orally with OVA alone.Orally administered TGF-beta retains sufficient biologic activity in intestinal mucosa and enhances oral tolerance.Oral administration of TGF-beta might become a potential strategy to prevent allergic diseases, such as food allergy.

    View details for DOI 10.1016/j.jaci.2007.05.023

    View details for Web of Science ID 000250157700028

    View details for PubMedID 17606291

  • Live imaging of Smad2/3 signaling in mouse skin wound healing WOUND REPAIR AND REGENERATION Chong, A. K., Satterwhite, T., Pham, H. M., Costa, M. A., Luo, J., Longaker, M. T., Wyss-Coray, T., Chang, J. 2007; 15 (5): 762-766


    Biophotonics and real-time imaging are novel technologies that can greatly enhance the study of complex biological processes. We applied this technology in a transgenic mouse with a luciferase reporter gene fused to a transforming growth factor-beta (TGF-beta) responsive Smad2/3-binding element to study bioluminescence after skin wounding. Two dorsal midline excisional skin wounds were made using a biopsy punch. One wound was randomized to suture closure and the other allowed to heal by secondary intention (n=8 each wound). Bioluminescence was measured at fixed time points following surgery. Phospho-Smad2/3 immunohistochemistry was performed to localize expression in skin wound samples. In vivo bioluminescence increased following skin wounding. Peak activity occurred on day 17 and was fourfold that of baseline (p<0.05). Subgroup analysis of primary and secondary healing showed that primarily sutured wounds had peak activities earlier than those with secondary healing, although this did not reach statistical significance. Intense phospho-Smad2/3 staining was found in the hair follicles. In vivo bioluminescence tracks Smad2/3-dependent TGF-beta signaling in the in vivo wound healing process. Our findings suggest that signaling increases after wound healing, which contrasts with other studies that show raised TGF-beta signaling in the initial days following wounding.

    View details for DOI 10.1111/j.1524-475X.2007.00299.x

    View details for Web of Science ID 000249846800019

    View details for PubMedID 17971023

  • Selective expansion of Foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells JOURNAL OF IMMUNOLOGY Matsumura, Y., Kobayashi, T., Ichiyama, K., Yoshida, R., Hashimoto, M., Takimoto, T., Tanaka, K., Chinen, T., Shichita, T., Wyss-Coray, T., Sato, K., Yoshimura, A. 2007; 179 (4): 2170-2179


    Dendritic cells (DCs) induce immunity and immunological tolerance as APCs. It has been shown that DCs secreting IL-10 induce IL-10(+) Tr1-type regulatory T (Treg) cells, whereas Foxp3-positive Treg cells are expanded from naive CD4(+) T cells by coculturing with mature DCs. However, the regulatory mechanism of expansion of Foxp3(+) Treg cells by DCs has not been clarified. In this study, we demonstrated that suppressors of cytokine signaling (SOCS)-3-deficient DCs have a strong potential as Foxp3(+) T cell-inducing tolerogenic DCs. SOCS3(-/-) DCs expressed lower levels of class II MHC, CD40, CD86, and IL-12 than wild-type (WT)-DCs both in vitro and in vivo, and showed constitutive activation of STAT3. Foxp3(-) effector T cells were predominantly expanded by the priming with WT-DCs, whereas Foxp3(+) Treg cells were selectively expanded by SOCS3(-/-) DCs. Adoptive transfer of SOCS3(-/-) DCs reduced the severity of experimental autoimmune encephalomyelitis. Foxp3(+) T cell expansion was blocked by anti-TGF-beta Ab, and SOCS3(-/-) DCs produced higher levels of TGF-beta than WT-DCs, suggesting that TGF-beta plays an essential role in the expansion of Foxp3(+) Treg cells. These results indicate an important role of SOCS3 in determining on immunity or tolerance by DCs.

    View details for Web of Science ID 000248959200019

    View details for PubMedID 17675476

  • In vitro analysis of transforming growth factor-beta 1 inhibition in novel Transgenic SBE-luciferase mice ANNALS OF PLASTIC SURGERY Satterwhite, T. S., Chong, A. K., Luo, J., Pham, H., Costa, M., Longaker, M. T., Wyss-Coray, T., Chang, J. 2007; 59 (2): 207-213


    Transforming growth factor beta1 (TGF-beta1) expression correlates with scarring. A novel transgenic mouse model with a Smad2/3-responsive luciferase reporter construct (SBE-luc) has been developed. We hypothesized that bioluminescence in SBE-luc dermal fibroblasts could be measured to assess TGF-beta1 inhibition.Cultured dermal fibroblasts from SBE-luc mice were treated simultaneously with TGF-beta1 and increasing doses of either neutralizing antibody to TGF-beta (NA-TGFbeta) or SB-431542, a novel TGF-beta receptor kinase inhibitor. Fibroblasts were measured for luciferase activity. SBE-luc fibroblasts underwent Western blot analysis for collagen type I production.TGF-beta1 produced maximal luciferase activity in SBE-luc fibroblasts at 0.1 ng/mL (P < 0.05). NA-TGFbeta and SB-431542 inhibited luciferase activity in a dose-dependent fashion, with complete inhibition achieved by 0.1 microg/mL and 1 microM, respectively (P < 0.05). NA-TGFbeta and SB-431542 inhibited collagen type I production.Our in vitro results provide validation for further in vivo real-time imaging studies using the SBE-luc mouse as a novel wound-healing model.

    View details for DOI 10.1097/

    View details for Web of Science ID 000248363400017

    View details for PubMedID 17667417

  • Immune cells may fend off Alzheimer disease NATURE MEDICINE Britschgi, M., Wyss-Coray, T. 2007; 13 (4): 408-409

    View details for Web of Science ID 000245543900015

    View details for PubMedID 17415372

  • Systemic and acquired immune responses in alzheimer's disease 9th Workshop on Apoptosis in Biology and Medicine on Neuroinflammation in Neuronal Death and Repair Britschgi, M., Wyss-Coray, T. ELSEVIER ACADEMIC PRESS INC. 2007: 205–233


    Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by a progressive cognitive decline and dementia. AD brains are marked by amyloid plaques and neurofibrillary tangles, neuronal cell loss, and a prominent activation of glial cells, and innate immune responses. A growing number of studies in AD have also reported alterations in systemic immune responses including changes in lymphocyte and macrophage distribution and activation, the presence of autoantibodies, or abnormal cytokine production. Studies in animal models for AD support the notion that immune cells infiltrate the brain and may modulate the disease. Here we will review evidence for systemic alterations in immune responses and a role for acquired immunity in AD and discuss their potential contribution to the disease.

    View details for DOI 10.1016/S0074-7742(07)82011-3

    View details for Web of Science ID 000248524100011

    View details for PubMedID 17678963

  • A role for TGF-beta signaling in neurodegeneration: evidence from genetically engineered models. Current Alzheimer research Tesseur, I., Wyss-Coray, T. 2006; 3 (5): 505-513


    Neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD) afflict growing numbers of people but treatments are not available or ineffective. These diseases are characterized by the loss of specific neuronal populations, the accumulation of protein aggregates inside and sometimes outside neurons, and an activation of immune pathways in the brain. The causes of sporadic forms of AD or PD are not known but it has been postulated that reduced trophic support to neurons together with age dependent increases in cellular stress lead to chronic injury and ultimately the demise of neurons. TGF-betas are neuroprotective factors and organizers of injury responses and as such might have a role in neurodegenerative disease. We review here the evidence mostly from genetically manipulated mice that links the TGF-beta signaling pathway to neuronal phenotypes and neurodegeneration. Although many of these mutant models did not produce overt CNS phenotypes or adult brain were not studied due to embryonic lethality, there is growing support for a role of TGF-beta signaling in neuronal maintenance, function, and degeneration. Future studies will have to determine whether dysregulation of TGF-beta signaling in neurodegenerative diseases is significant and whether this signaling pathway may even be a target for treatment.

    View details for PubMedID 17168649

  • Bioluminescence imaging of Smad signaling in living mice shows correlation with excitotoxic neurodegeneration PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Luo, J., Lin, A. H., Masliah, E., Wyss-Coray, T. 2006; 103 (48): 18326-18331


    The TGF-beta signaling pathway is a key organizer of injury and immune responses, and recent studies suggest it fulfills critical roles in CNS function and maintenance. TGF-beta receptor activation results in phosphorylation of Smad proteins, which subsequently translocate to the nucleus to regulate gene transcription by binding to Smad binding elements (SBE). Using SBE-luciferase reporter mice, we recently discovered that the brain has the highest Smad baseline activity of any major organ in the mouse, and we now demonstrate that this signal is primarily localized to pyramidal neurons of the hippocampus. In vivo excitatory stimulation with kainic acid (KA) resulted in an increase in luciferase activity and phosphorylated Smad2 (Smad2P), and nuclear translocation of Smad2P in hippocampal CA3 neurons correlated significantly with luciferase activity. Although this activation was most prominent at 24 h after KA administration in neurons, Smad2P immunoreactivity gradually increased in astrocytes and microglial cells at 3 and 5 days, consistent with reactive gliosis. Bioluminescence measured over the skull in living mice peaked at 12-72 h and correlated with the extent of microglial activation and pathological markers of neurodegeneration 5 days after injury. Treatment with the glutamate receptor antagonist MK-801 strongly reduced bioluminescence and pathology. These results show that Smad2 signaling is a sensitive marker of neuronal activation and CNS injury that can be used to monitor KA-induced neuronal degeneration. This and related mouse models may provide valuable tools to study mechanisms and treatments for neurodegeneration.

    View details for DOI 10.1073/pnas.0605077103

    View details for Web of Science ID 000242465200053

    View details for PubMedID 17110447

  • Increased T cell recruitment to the CNS after amyloid beta(1-42) immunization in Alzheimer's mice overproducing transforming growth factor-beta 1 JOURNAL OF NEUROSCIENCE Buckwalter, M. S., Coleman, B. S., Buttini, M., Barbour, R., Schenk, D., Games, D., Seubert, P., Wyss-Coray, T. 2006; 26 (44): 11437-11441


    Immunotherapy targeting the amyloid beta (Abeta) peptide is a novel therapy under investigation for the treatment of Alzheimer's disease (AD). A clinical trial using Abeta(1-42) (AN1792) as the immunogen was halted as a result of development of meningoencephalitis in a small number of patients. The cytokine TGF-beta1 is a key modulator of immune responses that is increased in the brain in AD. We show here that local overexpression of TGF-beta1 in the brain increases both meningeal and parenchymal T lymphocyte number. Furthermore, TGF-beta1 overexpression in a mouse model for AD [amyloid precursor protein (APP) mice] leads to development of additional T cell infiltrates when mice were immunized at a young but not old age with AN1792. Notably, only mice overproducing both Abeta (APP mice) and TGF-beta1 experienced a rise in T lymphocyte number after immunization. One-third of infiltrating T cells were CD4 positive. We did not observe significant differences in B lymphocyte numbers in any of the genotypes or treatment groups. These results demonstrate that TGF-beta1 overproduction in the brain can promote T cell infiltration, in particular after Abeta(1-42) immunization. Likewise, levels of TGF-beta1 or other immune factors in brains of AD patients may influence the response to Abeta(1-42) immunization.

    View details for DOI 10.1523/JNEUROSCI.2436-06.2006

    View details for Web of Science ID 000241727500024

    View details for PubMedID 17079673

  • Deficiency in neuronal TGF-beta signaling promotes neurodegeneratbn and Alzheimer's pathology JOURNAL OF CLINICAL INVESTIGATION Tesseur, I., Zou, K., Esposito, L., Bard, F., Berber, E., Van Can, J., Lin, A. H., Crews, L., Tremblay, P., Mathews, P., Mucke, L., Masliah, E., Wyss-Coray, T. 2006; 116 (11): 3060-3069


    Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cerebral accumulation of the beta-amyloid peptide (Abeta), but it is unknown what makes neurons susceptible to degeneration. We report that the TGF-beta type II receptor (TbetaRII) is mainly expressed by neurons, and that TbetaRII levels are reduced in human AD brain and correlate with pathological hallmarks of the disease. Reducing neuronal TGF-beta signaling in mice resulted in age-dependent neurodegeneration and promoted Abeta accumulation and dendritic loss in a mouse model of AD. In cultured cells, reduced TGF-beta signaling caused neuronal degeneration and resulted in increased levels of secreted Abeta and beta-secretase-cleaved soluble amyloid precursor protein. These results show that reduced neuronal TGF-beta signaling increases age-dependent neurodegeneration and AD-like disease in vivo. Increasing neuronal TGF-beta signaling may thus reduce neurodegeneration and be beneficial in AD.

    View details for DOI 10.1172/JCI27341

    View details for Web of Science ID 000241810900030

    View details for PubMedID 17080199

    View details for PubMedCentralID PMC1626127

  • Inflammation in Alzheimer disease: driving force, bystander or beneficial response? NATURE MEDICINE Wyss-Coray, T. 2006; 12 (9): 1005-1015


    Alzheimer disease is a progressive dementia with unknown etiology that affects a growing number of the aging population. Increased expression of inflammatory mediators in postmortem brains of people with Alzheimer disease has been reported, and epidemiological studies link the use of anti-inflammatory drugs with reduced risk for the disorder. On the initial basis of this kind of evidence, inflammation has been proposed as a possible cause or driving force of Alzheimer disease. If true, this could have important implications for the development of new treatments. Alternatively, inflammation could simply be a byproduct of the disease process and may not substantially alter its course. Or components of the inflammatory response might even be beneficial and slow the disease. To address these possibilities, we need to determine whether inflammation in Alzheimer disease is an early event, whether it is genetically linked with the disease and whether manipulation of inflammatory pathways changes the course of the pathology. Although there is still little evidence that inflammation triggers or promotes Alzheimer disease, increasing evidence from mouse models suggests that certain inflammatory mediators are potent drivers of the disease. Related factors, on the other hand, elicit beneficial responses and can reduce disease.

    View details for DOI 10.1038/nml1484

    View details for Web of Science ID 000240373900023

    View details for PubMedID 16960575

  • Tgf-Beta pathway as a potential target in neurodegeneration and Alzheimer's. Current Alzheimer research Wyss-Coray, T. 2006; 3 (3): 191-195


    Alzheimer's disease (AD) is a fatal neurodegenerative disease characterized by the loss of large numbers of forebrain neurons. There are currently no effective AD treatments available and the cause of the disease is unknown in the majority of cases. Because normal neuronal maintenance and survival depends on stimulation of key signaling pathways by a number of neurotrophic factors it has been postulated that reduced signaling by or expression of these factors may promote neurodegeneration. Growing evidence suggests that the transforming growth factor-beta (TGF-beta) signaling pathway may be one such neurotrophic pathway that meets important protective and survival roles in neurons. Here I explore this evidence and discuss the pathway as a potential target for the treatment of neurodegeneration and AD.

    View details for PubMedID 16842094

  • Neurodegeneration and neuroprotection in multiple sclerosis and other neurodegenerative diseases Symposium on Neuroprotective Strategies in Multiple Sclerosis Dhib-Jalbut, S., Arnold, D. L., Cleveland, D. W., Fisher, M., Friedlander, R. M., Mouradian, M. M., Przedborski, S., Trapp, B. D., Wyss-Coray, T., Yong, V. W. ELSEVIER SCIENCE BV. 2006: 198–215


    Multiple sclerosis is considered a disease of myelin destruction; Parkinson's disease (PD), one of dopaminergic neuron depletion; ALS, a disease of motor neuron death; and Alzheimer's, a disease of plaques and tangles. Although these disorders differ in important ways, they also have common pathogenic features, including inflammation, genetic mutations, inappropriate protein aggregates (e.g., Lewy bodies, amyloid plaques), and biochemical defects leading to apoptosis, such as oxidative stress and mitochondrial dysfunction. In most disorders, it remains uncertain whether inflammation and protein aggregation are neurotoxic or neuroprotective. Elucidating the mechanisms that orchestrate neuronal diseases should facilitate development of neuroprotective and neurorestorative strategies.

    View details for DOI 10.1016/j.jneuroim.2006.03.027

    View details for Web of Science ID 000240323300022

    View details for PubMedID 16983747

  • Chronically increased transforming growth factor-beta 1 strongly inhibits hippocampal neurogenesis in aged mice AMERICAN JOURNAL OF PATHOLOGY Buckwalter, M. S., Yamane, M., Coleman, B. S., Ormerod, B. K., Chin, J. T., Palmer, T., Wyss-Coray, T. 2006; 169 (1): 154-164


    There is increasing evidence that hippocampal learning correlates strongly with neurogenesis in the adult brain. Increases in neurogenesis after brain injury also correlate with improved outcomes. With aging the capacity to generate new neurons decreases dramatically, both under normal conditions and after injury. How this decrease occurs is not fully understood, but we hypothesized that transforming growth factor (TGF)-beta1, a cell cycle regulator that rapidly increases after injury and with age, might play a role. We found that chronic overproduction of TGF-beta1 from astrocytes almost completely blocked the generation of new neurons in aged transgenic mice. Even young adult TGF-beta1 mice had 60% fewer immature, doublecortin-positive, hippocampal neurons than wild-type littermate controls. Bromodeoxyuridine labeling of dividing cells in 2-month-old TGF-beta1 mice confirmed this decrease in neuro-genesis and revealed a similar decrease in astrogenesis. Treatment of early neural progenitor cells with TGF-beta1 inhibited their proliferation. This strongly suggests that TGF-beta1 directly affects these cells before their differentiation into neurons and astrocytes. Together, these data show that TGF-beta1 is a potent inhibitor of hippocampal neural progenitor cell proliferation in adult mice and suggest that it plays a key role in limiting injury and age-related neurogenesis.

    View details for DOI 10.2353/ajpath.2006.051272

    View details for Web of Science ID 000238664700014

    View details for PubMedID 16816369

  • Highly sensitive and specific bioassay for measuring bioactive TGF-beta BMC CELL BIOLOGY Tesseur, I., Zou, K., Berber, E., Zhang, H., Wyss-Coray, T. 2006; 7


    Transforming Growth Factor-beta (TGF-beta) regulates key biological processes during development and in adult tissues and has been implicated in many diseases. To study the biological functions of TGF-beta, sensitive, specific, and convenient bioassays are necessary. Here we describe a new cell-based bioassay that fulfills these requirements.Embryonic fibroblasts from Tgfb1-/- mice were stably transfected with a reporter plasmid consisting of TGF-beta responsive Smad-binding elements coupled to a secreted alkaline phosphatase reporter gene (SBE-SEAP). Clone MFB-F11 showed more than 1000-fold induction after stimulation with 1 ng/ml TGF-beta1, and detected as little as 1 pg/ml TGF-beta1. MFB-F11 cells were highly induced by TGF-beta1, TGF-beta2 and TGF-beta3, but did not show induction with related family members activin, nodal, BMP-2 and BMP-6 or with trophic factors bFGF and BDNF. MFB-F11 cells can detect and quantify TGF-beta in biological samples without prior enrichment of TGF-betas, and can detect biologically activated TGF-beta in a cell co-culture system.MFB-F11 cells can be used to rapidly and specifically measure TGF-beta with high sensitivity.

    View details for DOI 10.1186/1471-2121-7-15

    View details for Web of Science ID 000238363700001

    View details for PubMedID 16549026

  • Noninvasive bioluminescence imaging of neural injury and inflammation in mouse models 37th Annual Meeting of the American-Society-for-Neurochemistry Wyss-Coray, T., Luo, J. WILEY-BLACKWELL. 2006: 93–93
  • Global analysis of Smad2/3-dependent TGF-beta signaling in living mice reveals prominent tissue-specific responses to injury JOURNAL OF IMMUNOLOGY Lin, A. H., Luo, J., Mondshein, L. H., ten Dijke, P., Vivien, D., Contag, C. H., Wyss-Coray, T. 2005; 175 (1): 547-554


    Smad2 and Smad3 (Smad2/3) proteins are key signaling molecules for TGF-beta and some related family members regulating the transcription of several hundred genes. TGF-beta have key roles in development, tissue homeostasis, and the pathogenesis of many human diseases, including cancer, fibrotic disorders, developmental defects, and neurodegeneration. To study the temporal and spatial patterns of Smad2/3-dependent signaling in normal and pathological conditions in the living organism, we engineered transgenic mice with a Smad-responsive luciferase reporter construct (SBE-luc mice). Using bioluminescent imaging, we assessed Smad2/3 signaling activity noninvasively in living mice. At baseline, this activity was highest in brain, intestine, heart, and skin, and correlated with biochemical measurements of reporter activity. Primary astrocytes cultured from SBE-luc mice showed specific activation of the reporter in response to Smad2/3-activating TGF-beta family members. Treatment of mice with the endotoxin LPS resulted in a fast and vigorous, but transient activation of the reporter in the intestine. Although the response was similarly rapid in brain, it remained increased, indicating important but different cellular responses to endotoxin challenge in these organs. Traumatic brain injury with a needle stab resulted in local activation of Smad2/3-dependent genes and a severalfold increase in bioluminescence in living mice. SBE-luc mice can therefore be used to study temporal, tissue-specific activation of Smad2/3-dependent signaling in living mice in normal or pathological conditions as well as for the identification of endogenous or synthetic modulators of this pathway.

    View details for Web of Science ID 000230050900069

    View details for PubMedID 15972691

  • Reduced brain tissue perfusion in TGF-beta 1 transgenic mice showing Alzheimer's disease-like cerebrovascular abnormalities NEUROBIOLOGY OF DISEASE Gaertner, R. F., Wyss-Coray, T., Von Euw, D., Lesne, S., Vivien, D., Lacombe, P. 2005; 19 (1-2): 38-46


    We have studied the functional repercussions of cerebrovascular abnormalities in transgenic mice overexpressing TGF-beta1. These mice develop Alzheimer's disease-like vascular and meningeal alterations without parenchymal degeneration. Autoradiographic cerebral blood flow measurements in 9-month-old TGF-beta1 mice compared to non-transgenic littermates provided evidence of reduced tissue perfusion, most prominent in limbic regions. A highly significant inverse correlation was found between the density of thioflavin-S-positive blood vessels and blood flow in the hippocampus and the cortex. An inverse correlation was likewise found between meningeal staining and blood flow in thalamic nuclei and regions of high blood flow. Thus, the vascular abnormalities were associated locally with reduced perfusion rate and more widely with limitation in the blood flow. These chronic changes may be related to fibrillar and soluble A beta peptides, the amount of which was almost doubled in the brains of TGF-beta1 mice. Comparison with previous results of cerebral glucose utilization in TGF-beta1 mice shows that reduced utilization preferentially occurred in regions with a high metabolic rate and a relatively low blood flow, suggesting that the metabolic needs are not met by blood supply in these regions.

    View details for DOI 10.1016/j.nbd.2004.11.008

    View details for Web of Science ID 000228672900005

    View details for PubMedID 15837559

  • Killing pain, killing neurons? NATURE MEDICINE Wyss-Coray, T. 2005; 11 (5): 472-473

    View details for DOI 10.1038/nm0505-472

    View details for Web of Science ID 000228915000013

    View details for PubMedID 15875048

  • Small molecule tgf-beta mimetics as potential neuroprotective factors. Current Alzheimer research Zhang, H., Zou, K., Tesseur, I., Wyss-Coray, T. 2005; 2 (2): 183-186


    Neurodegenerative and dementing illnesses are becoming an increasing social and economical burden as the number of older people continues to grow in industrialized countries. Current knowledge of the processes leading to these diseases is still limited, and very few effective treatments are available. Because neurodegeneration is associated with an activation of injury and innate immune responses in the brain, drugs that could mimic the beneficial aspects of this response are potential therapeutic candidates. The cytokine transforming growth factor (TGF)-beta1 is an organizer of the brain's response to injury and is known to be neuroprotective. Previous studies from our lab also showed that TGF-beta1 can reduce accumulation of beta-amyloid peptide (Abeta), which appears to be central to Alzheimer's disease (AD) pathogenesis, and we therefore initiated a search for small molecule chemical compounds that could mimic this effect. We report here the identification of several such TGF-beta mimetics detected in an in vitro screen of a library with 5000 chemically diverse compounds. If active in vivo, these mimetics could be developed into candidates for the treatment of neurodegeneration.

    View details for PubMedID 15974916

  • Insights into the pathogenesis of hydrocephalus from transgenic and experimental animal models BRAIN PATHOLOGY Crews, L., Wyss-Coray, T., Masliah, E. 2004; 14 (3): 312-316


    Hydrocephalus is a progressive brain disorder characterized by abnormalities in the flow of cerebrospinal fluid (CSF) and ventricular dilatation that leads to cerebral atrophy, and if left untreated, can be fatal. Genetic mutations, congenital malformations, infectious diseases, intracerebral hemorrhages and tumors are common conditions resulting in hydrocephalus. Although the causes of obstructive hydrocephalus are better understood, the mechanisms resulting in chronic, progressive communicating congenital and acquired hydrocephalus are less well understood. In this regard, recent studies in transgenic (tg) mice suggest that increased expression of cytokines such as TGF-beta1 might play an important role by disrupting the vascular extracellular matrix (ECM) remodeling, promoting hemorrhages, and altering the reabsorption of CSF. In this context, the main objective of this manuscript is to provide an overview on the cellular and molecular mechanisms of hydrocephalus based on studies derived from tg and experimental animal models.

    View details for Web of Science ID 000223359400012

    View details for PubMedID 15446587

  • Inhibition of the TGF-beta signaling pathway results in increased neurodegeneration and amyloid deposition in human APP transgenic mice 9th International Conference on Alzheimers Disease and Related Disorders Tesseur, I. C., Zou, K., Masliah, E., Corn, J., Brionne, T., Bard, F., Wyss-Coray, T. ELSEVIER SCIENCE INC. 2004: S154–S154
  • Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice JOURNAL OF NEUROSCIENCE Brecht, W. J., Harris, F. M., Chang, S. J., Tesseur, I., Yu, G. Q., Xu, Q., Fish, J. D., Wyss-Coray, T., Buttini, M., Mucke, L., MAHLEY, R. W., Huang, Y. D. 2004; 24 (10): 2527-2534


    Apolipoprotein E (apoE) is found in amyloid plaques and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains, but its role in their pathogenesis is unclear. Previously, we found C-terminal-truncated fragments of apoE in AD brains and showed that such fragments can cause neurodegeneration and can induce NFT-like inclusions in cultured neuronal cells and in transgenic mice. Here, we analyzed apoE fragmentation in brain tissue homogenates from transgenic mice expressing apoE3 or apoE4 in neurons [neuron-specific enolase (NSE)-apoE] or astrocytes [glial fibrillary acidic protein (GFAP)-apoE] by Western blotting. The C-terminal-truncated fragments of apoE accumulated, in an age-dependent manner, in the brains of NSE-apoE4 and, to a significantly lesser extent, NSE-apoE3 mice; however, no fragments were detected in GFAP-apoE3 or GFAP-apoE4 mice. In NSE-apoE mice, the pattern of apoE fragmentation resembled that seen in AD brains, and the fragmentation was specific for certain brain regions, occurring in the neocortex and hippocampus, which are vulnerable to AD-related neurodegeneration, but not in the less vulnerable cerebellum. Excitotoxic challenge with kainic acid significantly increased apoE fragmentation in NSE-apoE4 but not NSE-apoE3 mice. Phosphorylated tau (p-tau) also accumulated in an age-dependent manner in NSE-apoE4 mice and, to a much lesser extent, in NSE-apoE3 mice but not in GFAP-apoE3 or GFAP-apoE4 mice. Intraneuronal p-tau inclusions in the hippocampus were prominent in 21-month-old NSE-apoE4 mice but barely detectable in NSE-apoE3 mice. Thus, the accumulation of potentially pathogenic C-terminal-truncated fragments of apoE depends on both the isoform and the cellular source of apoE. Neuron-specific proteolytic cleavage of apoE4 is associated with increased phosphorylation of tau and may play a key role in the development of AD-related neuronal deficits.

    View details for DOI 10.1523/JNEUROSCI.4315-03.2004

    View details for Web of Science ID 000220129800020

    View details for PubMedID 15014128

  • Astroglial regulation of apolipoprotein E expression in neuronal cells - Implications for Alzheimer's disease JOURNAL OF BIOLOGICAL CHEMISTRY Harris, F. M., Tesseur, I., Brecht, W. J., Xu, Q., Mullendorff, K., Chang, S. J., Wyss-Coray, T., MAHLEY, R. W., Huang, Y. D. 2004; 279 (5): 3862-3868


    Although apolipoprotein (apo) E is synthesized in the brain primarily by astrocytes, neurons in the central nervous system express apoE, albeit at lower levels than astrocytes, in response to various physiological and pathological conditions, including excitotoxic stress. To investigate how apoE expression is regulated in neurons, we transfected Neuro-2a cells with a 17-kilobase human apoE genomic DNA construct encoding apoE3 or apoE4 along with upstream and downstream regulatory elements. The baseline expression of apoE was low. However, conditioned medium from an astrocytic cell line (C6) or from apoE-null mouse primary astrocytes increased the expression of both isoforms by 3-4-fold at the mRNA level and by 4-10-fold at the protein level. These findings suggest that astrocytes secrete a factor or factors that regulate apoE expression in neuronal cells. The increased expression of apoE was almost completely abolished by incubating neurons with U0126, an inhibitor of extracellular signal-regulated kinase (Erk), suggesting that the Erk pathway controls astroglial regulation of apoE expression in neuronal cells. Human neuronal precursor NT2/D1 cells expressed apoE constitutively; however, after treatment of these cells with retinoic acid to induce differentiation, apoE expression diminished. Cultured mouse primary cortical and hippocampal neurons also expressed low levels of apoE. Astrocyte-conditioned medium rapidly up-regulated apoE expression in fully differentiated NT2 neurons and in cultured mouse primary cortical and hippocampal neurons. Thus, neuronal expression of apoE is regulated by a diffusible factor or factors released from astrocytes, and this regulation depends on the activity of the Erk kinase pathway in neurons.

    View details for DOI 10.1074/jbc.M309475200

    View details for Web of Science ID 000188379600088

    View details for PubMedID 14585838

  • Modelling neuroinflammatory phenotypes in vivo. Journal of neuroinflammation Buckwalter, M. S., Wyss-Coray, T. 2004; 1 (1): 10


    Inflammation of the central nervous system is an important but poorly understood part of neurological disease. After acute brain injury or infection there is a complex inflammatory response that involves activation of microglia and astrocytes and increased production of cytokines, chemokines, acute phase proteins, and complement factors. Antibodies and T lymphocytes may be involved in the response as well. In neurodegenerative disease, where injury is more subtle but consistent, the inflammatory response is continuous. The purpose of this prolonged response is unclear, but it is likely that some of its components are beneficial and others are harmful. Animal models of neurological disease can be used to dissect the specific role of individual mediators of the inflammatory response and assess their potential benefit. To illustrate this approach, we discuss how mutant mice expressing different levels of the cytokine transforming growth factor beta-1 (TGF-beta1), a major modulator of inflammation, produce important neuroinflammatory phenotypes. We then demonstrate how crosses of TGF-beta1 mutant mice with mouse models of Alzheimer's disease (AD) produced important new information on the role of inflammation in AD and on the expression of different neuropathological phenotypes that characterize this disease.

    View details for DOI 10.1186/1742-2094-1-10

    View details for PubMedID 15285805

  • Modelling neuroinflammatory phenotypes in vivo JOURNAL OF NEUROINFLAMMATION Buckwalter, M. S., Wyss-Coray, T. 2004; 1
  • Transforming growth factor-beta signaling pathway as a therapeutic target in neurodegeneration JOURNAL OF MOLECULAR NEUROSCIENCE Wyss-Coray, T. 2004; 24 (1): 149-153


    Neurodegenerative diseases are becoming an increasing social and economical burden as our population ages; but current knowledge of the processes leading to these diseases is still limited, and no effective treatments are available. Neurodegeneration in Alzheimer's disease (AD) is the most common cause of dementia and afflicts an estimated 4 million people in this country alone. Because accumulation of beta-amyloid (Abeta) peptide appears central to AD pathogenesis, large efforts have been directed at understanding and interfering with Abeta production or aggregation. These efforts have largely identified the processes resulting in Abeta production from the larger amyloid precursor protein (APP) and have revealed that Abeta peptide is also produced at low levels in the healthy brain. Interestingly, Abeta production is rapidly increased after neuronal injury, and traumatic brain injury is a known risk factor for AD and Parkinson's disease. In contrast, brain injury in young individuals does not seem to result in AD, and brain injury in animal models can promote Abeta clearance. This suggests that certain factors associated with injury might be able to reduce the accumulation of Abeta. Accumulation of Abeta peptide might be reduced either directly by stimulating phagocytes or other Abeta-degrading processes, or indirectly, by reducing neuronal injury and thus lowering the production of Abeta peptide. Directing the brain's natural mechanisms for clearing Abeta or increasing neuroprotection might therefore be reasonable approaches in interfering with AD pathogenesis.

    View details for Web of Science ID 000223521700022

    View details for PubMedID 15314264

  • Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain NEURON Brionne, T. C., Tesseur, I., Masliah, E., Wyss-Coray, T. 2003; 40 (6): 1133-1145


    TGF-beta1 is a key regulator of diverse biological processes in many tissues and cell types, but its exact function in the developing and adult mammalian CNS is still unknown. We report that lack of TGF-beta1 expression in neonatal Tgfb1(-/-) mice results in a widespread increase in degenerating neurons accompanied by reduced expression of synaptophysin and laminin and a prominent microgliosis. Lack of TGF-beta1 also strongly reduces survival of primary neurons cultured from Tgfb1(-/-) mice. TGF-beta1 deficiency in adult Tgfb1(-/+) mice results in increased neuronal susceptibility to excitotoxic injury, whereas astroglial overexpression of TGF-beta1 protects adult mice against neurodegeneration in acute, excitotoxic and chronic injury paradigms. This study reveals a nonredundant function for TGF-beta1 in maintaining neuronal integrity and survival of CNS neurons and in regulating microglial activation. Because individual TGF-beta1 expression levels in the brain vary considerably between humans, this finding could have important implications for susceptibility to neurodegeneration.

    View details for Web of Science ID 000187503400012

    View details for PubMedID 14687548

  • Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Harris, F. M., Brecht, W. J., Xu, Q., Tesseur, I., Kekonius, L., Wyss-Coray, T., Fish, J. D., Masliah, E., Hopkins, P. C., Scearce-Levie, K., Weisgraber, K. H., Mucke, L., MAHLEY, R. W., Huang, Y. D. 2003; 100 (19): 10966-10971


    Apolipoprotein (apo) E4 increases the risk and accelerates the onset of Alzheimer's disease (AD). However, the underlying mechanisms remain to be determined. We previously found that apoE undergoes proteolytic cleavage in AD brains and in cultured neuronal cells, resulting in the accumulation of carboxyl-terminal-truncated fragments of apoE that are neurotoxic. Here we show that this fragmentation is caused by proteolysis of apoE by a chymotrypsin-like serine protease that cleaves apoE4 more efficiently than apoE3. Transgenic mice expressing the carboxyl-terminal-cleaved product, apoE4(Delta272-299), at high levels in the brain died at 2-4 months of age. The cortex and hippocampus of these mice displayed AD-like neurodegenerative alterations, including abnormally phosphorylated tau (p-tau) and Gallyas silver-positive neurons that contained cytosolic straight filaments with diameters of 15-20 nm, resembling preneurofibrillary tangles. Transgenic mice expressing lower levels of the truncated apoE4 survived longer but showed impaired learning and memory at 6-7 months of age. Thus, carboxyl-terminal-truncated fragments of apoE4, which occur in AD brains, are sufficient to elicit AD-like neurodegeneration and behavioral deficits in vivo. Inhibiting their formation might inhibit apoE4-associated neuronal deficits.

    View details for DOI 10.1073/pnas.1434398100

    View details for Web of Science ID 000185415300070

    View details for PubMedID 12939405

  • Adult mouse astrocytes degrade amyloid-beta in vitro and in situ NATURE MEDICINE Wyss-Coray, T., Loike, J. D., Brionne, T. C., Lu, E., Anankov, R., Yan, F. R., Silverstein, S. C., Husemann, J. 2003; 9 (4): 453-457


    Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of Abeta deposition, but the cause or significance of this cellular response is unclear. Here we show that cultured adult mouse astrocytes migrate in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD lesions, and cease migration upon interaction with immobilized Abeta(1-42). We also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on Abeta-laden brain sections from a mouse model of AD associate with the Abeta deposits and reduce overall Abeta levels in these sections. Our results suggest a novel mechanism for the accumulation of astrocytes around Abeta deposits, indicate a direct role for astrocytes in degradation of Abeta and implicate deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments that increase removal of Abeta by astrocytes may therefore be a critical mechanism to reduce the neurodegeneration associated with AD.

    View details for DOI 10.1038/nm838

    View details for Web of Science ID 000181987400036

    View details for PubMedID 12612547

  • Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wyss-Coray, T., Yan, F. R., Lin, A. H., Lambris, J. D., Alexander, J. J., Quigg, R. J., Masliah, E. 2002; 99 (16): 10837-10842


    Abnormal accumulation of beta-amyloid (Abeta) in Alzheimer's disease (AD) is associated with prominent brain inflammation. Whereas earlier studies concluded that this inflammation is detrimental, more recent animal data suggest that at least some inflammatory processes may be beneficial and promote Abeta clearance. Consistent with these observations, overproduction of transforming growth factor (TGF)-beta1 resulted in a vigorous microglial activation that was accompanied by at least a 50% reduction in Abeta accumulation in human amyloid precursor protein (hAPP) transgenic mice. In a search for inflammatory mediators associated with this reduced pathology, we found that brain levels of C3, the central component of complement and a key inflammatory protein activated in AD, were markedly higher in hAPP/TGF-beta1 mice than in hAPP mice. To assess the importance of complement in the pathogenesis of AD-like disease in mice, we inhibited C3 activation by expressing soluble complement receptor-related protein y (sCrry), a complement inhibitor, in the brains of hAPP mice. Abeta deposition was 2- to 3-fold higher in 1-year-old hAPP/sCrry mice than in age-matched hAPP mice and was accompanied by a prominent accumulation of degenerating neurons. These results indicate that complement activation products can protect against Abeta-induced neurotoxicity and may reduce the accumulation or promote the clearance of amyloid and degenerating neurons. These findings provide evidence for a role of complement and innate immune responses in AD-like disease in mice and support the concept that certain inflammatory defense mechanisms in the brain may be beneficial in neurodegenerative disease.

    View details for DOI 10.1073/pnas.162350199

    View details for Web of Science ID 000177343200110

    View details for PubMedID 12119423

  • Inflammation in neurodegenerative disease - A double-edged sword NEURON Wyss-Coray, T., Mucke, L. 2002; 35 (3): 419-432


    Inflammation is a defense reaction against diverse insults, designed to remove noxious agents and to inhibit their detrimental effects. It consists of a dazzling array of molecular and cellular mechanisms and an intricate network of controls to keep them in check. In neurodegenerative diseases, inflammation may be triggered by the accumulation of proteins with abnormal conformations or by signals emanating from injured neurons. Given the multiple functions of many inflammatory factors, it has been difficult to pinpoint their roles in specific (patho)physiological situations. Studies of genetically modified mice and of molecular pathways in activated glia are beginning to shed light on this issue. Altered expression of different inflammatory factors can either promote or counteract neurodegenerative processes. Since many inflammatory responses are beneficial, directing and instructing the inflammatory machinery may be a better therapeutic objective than suppressing it.

    View details for Web of Science ID 000177331200005

    View details for PubMedID 12165466

  • Molecular and functional dissection of TGF-beta 1-induced cerebrovascular abnormalities in transgenic mice 3rd World Congress on Vascular Factors in Alzheimers Disease Buckwalter, M., Pepper, J. P., Gaertner, R. F., Von Euw, D., Lacombe, P., Wyss-Coray, T. NEW YORK ACAD SCIENCES. 2002: 87–95


    Cerebrovascular abnormalities, such as reduced blood flow, microvascular fibrosis, and cerebrovascular amyloid angiopathy, are prominent in Alzheimer's disease (AD). However, their etiology is poorly understood and it is unclear whether cerebrovascular changes contribute to functional impairments in the absence of neurodegeneration. In humans with AD, transforming growth factor-beta1 (TGF-beta1) mRNA levels in the midfrontal gyrus correlate positively with the relative degree of cerebrovascular amyloid deposition in that brain region, suggesting a possible role for TGF-beta1 in human cerebrovascular abnormalities. Transgenic mice overexpressing TGF-beta1 in astrocytes develop AD-like cerebrovascular abnormalities, including perivascular astrocytosis, microvascular basement membrane thickening, and accumulation of thioflavin S-positive amyloid in the absence of parenchymal degeneration. Mice overexpressing TGF-beta1 alone or in addition to human amyloid precursor protein (hAPP) show selective accumulation of human beta-amyloid (Abeta) in blood vessels and develop cerebral hemorrhages in old age. In 9-month-old TGF-beta1 transgenic mice, cerebral blood flow (CBF) in the limbic system was significantly less than in nontransgenic littermate controls. Aged TGF-beta1 mice also showed overall reduced cerebral glucose uptake (CGU) as a measure of brain activity. Thus, chronic overproduction of TGF-beta1 in the brain results in structural and functional impairments reminiscent of those in AD cases with amyloid angiopathy.

    View details for Web of Science ID 000179767000009

    View details for PubMedID 12480736

  • Functional role of TGF beta in Alzheimer's disease microvascular injury: lessons from transgenic mice NEUROCHEMISTRY INTERNATIONAL Masliah, E., Ho, G., Wyss-Coray, T. 2001; 39 (5-6): 393-400


    Recent studies have implicated pro- and anti-inflammatory cytokines as integral to Alzheimer's disease (AD) pathogenesis. Among them, transforming growth factor-beta (TGF-beta) is emerging as an important factor in regulating inflammatory responses. This multifunctional cytokine might be centrally involved in several aspects of AD pathogenesis by regulating beta-amyloid precursor protein synthesis and processing, plaque formation, astroglial and microglial response and neuronal cell death. Among all of these potential roles, studies in transgenic and infusion animal models have shown that TGF-beta may primarily contribute to AD pathogenesis by influencing A beta production and deposition, which in turn might result in damage to the brain microvasculature. The lessons learned from these models are of great interest not only for understanding of the role of TGF-beta in AD, but also for future treatments where testing of anti-inflammatory agents such as ibuprofen and an amyloid vaccine hold great promise. In this regard, further elucidation of the signal pathways by which TGF-beta exerts its effect in AD might lead to specific targets for further therapeutic intervention.

    View details for Web of Science ID 000172052700008

    View details for PubMedID 11578774

  • Key signaling pathways regulate the biological activities and accumulation of amyloid-beta NEUROBIOLOGY OF AGING Wyss-Coray, T., MCCONLOGUE, L., Kindy, M., Schmidt, A. M., Yan, S. D., Stern, D. M. 2001; 22 (6): 967-973

    View details for Web of Science ID 000173026100020

    View details for PubMedID 11755005

  • Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Huang, Y. D., Liu, X. Q., Wyss-Coray, T., Brecht, W. J., Sanan, D. A., MAHLEY, R. W. 2001; 98 (15): 8838-8843


    Human apolipoprotein (apo) E4, a major risk factor for Alzheimer's disease (AD), occurs in amyloid plaques and neurofibrillary tangles (NFTs) in AD brains; however, its role in the pathogenesis of these lesions is unclear. Here we demonstrate that carboxyl-terminal-truncated forms of apoE, which occur in AD brains and cultured neurons, induce intracellular NFT-like inclusions in neurons. These cytosolic inclusions were composed of phosphorylated tau, phosphorylated neurofilaments of high molecular weight, and truncated apoE. Truncated apoE4, especially apoE4(Delta 272--299), induced inclusions in up to 75% of transfected neuronal cells, but not in transfected nonneuronal cells. ApoE4 was more susceptible to truncation than apoE3 and resulted in much greater intracellular inclusion formation. These results suggest that apoE4 preferentially undergoes intracellular processing, creating a bioactive fragment that interacts with cytoskeletal components and induces NFT-like inclusions containing phosphorylated tau and phosphorylated neurofilaments of high molecular weight in neurons.

    View details for Web of Science ID 000169967000112

    View details for PubMedID 11447277

  • TGF-beta 1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice NATURE MEDICINE Wyss-Coray, T., Lin, C., Yan, F. R., Yu, G. Q., Rohde, M., MCCONLOGUE, L., Masliah, E., Mucke, L. 2001; 7 (5): 612-618


    Abnormal accumulation of the amyloid-beta peptide (Abeta) in the brain appears crucial to pathogenesis in all forms of Alzheimer disease (AD), but the underlying mechanisms in the sporadic forms of AD remain unknown. Transforming growth factor beta1 (TGF-beta1), a key regulator of the brain's responses to injury and inflammation, has been implicated in Abeta deposition in vivo. Here we demonstrate that a modest increase in astroglial TGF-beta1 production in aged transgenic mice expressing the human beta-amyloid precursor protein (hAPP) results in a three-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall Abeta load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing hAPP and TGF-beta1, Abeta accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human cases of AD, Abeta immunoreactivity associated with parenchymal plaques was inversely correlated with Abeta in blood vessels and cortical TGF-beta1 mRNA levels. The reduction of parenchymal plaques in hAPP/TGF-beta1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Recombinant TGF-beta1 stimulated Abeta clearance in microglial cell cultures. These results demonstrate that TGF-beta1 is an important modifier of amyloid deposition in vivo and indicate that TGF-beta1 might promote microglial processes that inhibit the accumulation of Abeta in the brain parenchyma.

    View details for Web of Science ID 000169961100042

    View details for PubMedID 11329064

  • Ibuprofen, inflammation and Alzheimer disease NATURE MEDICINE Wyss-Coray, T., Mucke, L. 2000; 6 (9): 973-974

    View details for Web of Science ID 000089190500023

    View details for PubMedID 10973311

  • Inflammation and Alzheimer's disease NEUROBIOLOGY OF AGING Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., Cooper, N. R., Eikelenboom, P., Emmerling, M., Fiebich, B. L., Finch, C. E., Frautschy, S., Griffin, W. S., Hampel, H., Hull, M., Landreth, G., Lue, L. F., Mrak, R., Mackenzie, I. R., McGeer, P. L., O'Banion, M. K., Pachter, J., Pasinetti, G., Plata-Salaman, C., Rogers, J., Rydel, R., Shen, Y., Streit, W., Strohmeyer, R., Tooyoma, I., van Muiswinkel, F. L., Veerhuis, R., Walker, D., Webster, S., Wegrzyniak, B., Wenk, G., Wyss-Coray, T. 2000; 21 (3): 383-421


    Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

    View details for Web of Science ID 000088059000001

    View details for PubMedID 10858586

  • Chronic overproduction of transforming growth factor-beta 1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice AMERICAN JOURNAL OF PATHOLOGY Wyss-Coray, T., Lin, C., Sanan, D. A., Mucke, L., Masliah, E. 2000; 156 (1): 139-150


    Cerebrovascular amyloid deposition and microvascular degeneration are frequently associated with Alzheimer's disease (AD), but the etiology and pathogenetic role of these abnormalities are unknown. Recently, transforming growth factor-beta1 (TGF-beta1) was implicated in cerebrovascular amyloid formation in transgenic mice with astroglial overproduction of TGF-beta1 and in AD. We tested whether TGF-beta1 overproduction induces AD-like cerebrovascular degeneration and analyzed how cerebrovascular abnormalities develop over time in TGF-beta1-transgenic mice. In cerebral microvessels from 3- to 4-month-old TGF-beta1-transgenic mice, which display a prominent perivascular astrocytosis, levels of the basement membrane proteins perlecan and fibronectin were severalfold higher than in vessels from nontransgenic mice. Consistent with this increase, cortical capillary basement membranes of TGF-beta1 mice were significantly thickened. These changes preceded amyloid deposition, which began at around 6 months of age. In 9- and 18-month-old TGF-beta1 mice, various degenerative changes in microvascular cells of the brain were observed. Endothelial cells were thinner and displayed abnormal, microvilli-like protrusions as well as occasional condensation of chromatin, and pericytes occupied smaller areas in capillary profiles than in nontransgenic controls. Similar cerebrovascular abnormalities have been reported in AD. We conclude that chronic overproduction of TGF-beta1 triggers an accumulation of basement membrane proteins and results in AD-like cerebrovascular amyloidosis and microvascular degeneration. Closely related processes may induce cerebrovascular pathology in AD.

    View details for Web of Science ID 000084773300017

    View details for PubMedID 10623661

  • Alzheimer's disease-like cerebrovascular pathology in transforming growth factor-beta 1 transgenic mice and functional metabolic correlates Conference on Vascular Factors in Alzheimers Disease Wyss-Coray, T., Lin, C., Von Euw, D., Masliah, E., Mucke, L., Lacombe, P. NEW YORK ACAD SCIENCES. 2000: 317–323


    Alzheimer's disease (AD) is frequently associated with cerebrovascular changes, including perivascular astrocytosis, amyloid deposition, and microvascular degeneration, but it is not known whether these pathological changes contribute to functional deficits in AD. To characterize the temporal relationship between amyloid deposition, cerebrovascular abnormalities, and potential functional changes, we studied transgenic mice that express transforming growth factor-beta 1 (TGF-beta 1) at low levels in astrocytes. TGF-beta 1 induced a prominent perivascular astrocytosis, followed by the accumulation of basement membrane proteins in microvessels, thickening of capillary basement membranes, and later, around 6 months of age, deposition of amyloid in cerebral blood vessels. At 9 months of age, various AD-like degenerative alterations were observed in endothelial cells and pericytes. Associated with these morphological changes were changes in regional cerebral glucose utilization. Preliminary results showed that TGF-beta 1 mice had significantly decreased glucose utilization in the mammillary bodies, structures involved in mnemonic and learning processes. Glucose utilization tended to be decreased in several other brain regions as well; however, in the inferior colliculus, it was markedly higher in TGF-beta 1 mice than in controls. We conclude that chronic overproduction of TGF-beta 1 triggers a pathogenic cascade leading to AD-like cerebrovascular amyloidosis, microvascular degeneration, and local alterations in brain metabolic activity. Similar mechanisms may be involved in AD pathogenesis.

    View details for Web of Science ID 000087756800041

    View details for PubMedID 10818521

  • Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease NEUROSCIENCE Buttini, M., Akeefe, H., Lin, C., MAHLEY, R. W., Pitas, R. E., Wyss-Coray, T., Mucke, L. 2000; 97 (2): 207-210


    Apolipoprotein E fulfills fundamental functions in lipid transport and neural tissue repair after injury.(6,8) Its three most common isoforms (E2, E3, and E4) are critical determinants of diverse human diseases, including major cardiovascular and neurodegenerative disorders.(8,14) Apolipoprotein E4 is associated with an increased risk for Alzheimer's disease(3,5) and poor clinical outcome after head injury or stroke.(11,16) The precise role of apolipoprotein E4 in these conditions remains unknown. To characterize the effects of human apolipoprotein E isoforms in vivo, we analysed transgenic Apoe knockout mice that express apolipoprotein E3 or E4 or both in the brain. Hemizygous and homozygous apolipoprotein E3 mice were protected against age-related and excitotoxin-induced neurodegeneration, whereas apolipoprotein E4 mice were not. Apolipoprotein E3/E4 bigenic mice were as susceptible to neurodegeneration as apolipoprotein E4 singly-transgenic mice. At eight months of age neurodegeneration was more severe in homozygous than in hemizygous apolipoprotein E4 mice consistent with a dose effect. Thus, apolipoprotein E4 is not only less neuroprotective than apolipoprotein E3 but also acts as a dominant negative factor that interferes with the beneficial function of apolipoprotein E3. The inhibition of this apolipoprotein E4 activity may be critical for the prevention and treatment of neurodegeneration in APOE varepsilon4 carriers.

    View details for Web of Science ID 000087064400001

    View details for PubMedID 10799751

  • Elimination of the class a scavenger receptor does not affect amyloid plaque formation or neurodegeneration in transgenic mice expressing human amyloid protein precursors AMERICAN JOURNAL OF PATHOLOGY Huang, F., Buttini, M., Wyss-Coray, T., MCCONLOGUE, L., Kodama, T., Pitas, R. E., Mucke, L. 1999; 155 (5): 1741-1747


    The class A scavenger receptor (SR) is expressed on reactive microglia surrounding cerebral amyloid plaques in Alzheimer's disease (AD). Interactions between the SR and amyloid beta peptides (Abeta) in microglial cultures elicit phagocytosis of Abeta aggregates and release of neurotoxins. To assess the role of the SR in amyloid clearance and Abeta-associated neurodegeneration in vivo, we used the platelet-derived growth factor promoter to express human amyloid protein precursors (hAPPs) in neurons of transgenic mice. With increasing age, hAPP mice develop AD-like amyloid plaques. We bred heterozygous hAPP (hAPP(+/-)) mice that were wild type for SR (SR(+/+)) with SR knockout (SR(-/-)) mice. Crosses among the resulting hAPP(+/-)SR(+/-) offspring yielded hAPP(+/-) and hAPP(-/-) littermates that were SR(+/+) or SR(-/-). These second-generation mice were analyzed at 6 and 12 months of age for extent of cerebral amyloid deposition and loss of synaptophysin-immunoreactive presynaptic terminals. hAPP(-/-)SR(-/-) mice showed no lack of SR expression, plaque formation, or synaptic degeneration, indicating that lack of SR expression does not result in significant accumulation of endogenous amyloidogenic or neurotoxic factors. In hAPP(+/-) mice, ablation of SR expression did not alter number, extent, distribution, or age-dependent accumulation of plaques; nor did it affect synaptic degeneration. Our results do not support a critical pathogenic role for microglial SR expression in neurodegenerative alterations associated with cerebral beta amyloidosis.

    View details for Web of Science ID 000083587600039

    View details for PubMedID 10550330

  • Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Xu, X., Yang, D. S., Wyss-Coray, T., Yan, J., Gan, L., Sun, Y., Mucke, L. 1999; 96 (13): 7547-7552


    Amyloid precursor proteins (APPs) are expressed in multiple organs and cell types in diverse species. Their conservation across species and high abundance in brain and the association of various APP missense mutations with autosomal dominant forms of familial Alzheimer's disease (FAD) suggest important roles for APP in the central nervous system. However, the basic functions of APP in the central nervous system remain largely unknown. To assess potential effects of APP on neuronal death and survival, we transfected APP-deficient rat neuroblastoma cells (B103) with DNA constructs encoding wild-type or FAD-mutant human APP. Wild-type, but not FAD-mutant, APP effectively protected cells against apoptosis induced by ultraviolet irradiation, staurosporine, or p53. Wild-type APP also strongly inhibited p53 DNA-binding activity and p53-mediated gene transactivation, whereas FAD-mutant APP did not. We conclude that APP protects neuronal cells against apoptosis by controlling p53 activation at the post-translational level. Disruption of this function by mutations or alterations in APP processing could enhance neuronal vulnerability to secondary insults and contribute to neuronal degeneration.

    View details for Web of Science ID 000081056000078

    View details for PubMedID 10377452

  • Expression of human apolipoprotein E3 or E4 in the brains of Apoe(-/-) mice: Isoform-specific effects on neurodegeneration JOURNAL OF NEUROSCIENCE Buttini, M., Orth, M., Bellosta, S., Akeefe, H., Pitas, R. E., Wyss-Coray, T., Mucke, L., MAHLEY, R. W. 1999; 19 (12): 4867-4880


    Apolipoprotein (apo) E isoforms are key determinants of susceptibility to Alzheimer's disease. The apoE4 isoform is the major known genetic risk factor for this disease and is also associated with poor outcome after acute head trauma or stroke. To test the hypothesis that apoE3, but not apoE4, protects against age-related and excitotoxin-induced neurodegeneration, we analyzed apoE knockout (Apoe-/-) mice expressing similar levels of human apoE3 or apoE4 in the brain under control of the neuron-specific enolase promoter. Neuronal apoE expression was widespread in the brains of these mice. Kainic acid-challenged wild-type or Apoe-/- mice had a significant loss of synaptophysin-positive presynaptic terminals and microtubule-associated protein 2-positive neuronal dendrites in the neocortex and hippocampus, and a disruption of neurofilament-positive axons in the hippocampus. Expression of apoE3, but not of apoE4, protected against this excitotoxin-induced neuronal damage. ApoE3, but not apoE4, also protected against the age-dependent neurodegeneration seen in Apoe-/- mice. These differences in the effects of apoE isoforms on neuronal integrity may relate to the increased risk of Alzheimer's disease and to the poor outcome after head trauma and stroke associated with apoE4 in humans.

    View details for Web of Science ID 000080753800019

    View details for PubMedID 10366621

  • Induction of matrix metalloproteinase-2 in human immunodeficiency virus-1 glycoprotein 120 transgenic mouse brains NEUROSCIENCE LETTERS Marshall, D. C., Wyss-Coray, T., Abraham, C. R. 1998; 254 (2): 97-100


    Human immunodeficiency virus (HIV)-1 can invade the brain and cause degeneration of the central nervous system, resulting in a host of cognitive and motor impairments. HIV-1 glycoprotein 120 (gp120), has been implicated in the neurodegenerative effects of HIV infection. Here, gp120's neurotoxic potential is demonstrated in both transgenic mice and cultured cells. We observed that gp120 causes an induction of matrix metalloproteinase (MMP)-2 activity and protein in transgenic mouse brains and in transfected C6 cells. We propose that induced MMP-2 may contribute to a neurodegenerative environment by degrading extracellular matrix (ECM) fibronectin and type IV collagen.

    View details for Web of Science ID 000076198300009

    View details for PubMedID 9779929

  • Novel role of human CD4 molecule identified in neurodegeneration NATURE MEDICINE Buttini, M., Westland, C. E., Masliah, E., Yafeh, A. M., Wyss-Coray, T., Mucke, L. 1998; 4 (4): 441-446


    The human CD4 molecule (hCD4) is expressed on T lymphocytes and macrophages and acts as a key component of the cellular receptor for HIV. At baseline, hCD4 transgenic mice expressed hCD4 on microglia, the resident mononuclear phagocytes of the brain, and showed no neuronal damage. Activation of brain microglia by peripheral immune challenges elicited neurodegeneration in hCD4 mice but not in nontransgenic controls. In post-mortem brain tissues from AIDS patients with opportunistic infections, but without typical HIV encephalitis, hCD4 expression correlated with neurodegeneration. We conclude that hCD4 may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system.

    View details for Web of Science ID 000072906800039

    View details for PubMedID 9546790

  • Amyloidogenic role of cytokine TGF-beta 1 in transgenic mice and in Alzheimer's disease NATURE WYSSCORAY, T., Masliah, E., Mallory, M., MCCONLOGUE, L., JOHNSONWOOD, K., Lin, C., Mucke, L. 1997; 389 (6651): 603-606


    Deposition of amyoid-beta peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-beta peptide are not known. The transforming growth factor TGF-beta1 plays a central role in the response of the brain to injury, and increased TGF-beta1 has been found in the central nervous system of patients with Alzheimer's disease. Here we report that TGF-beta1 induces amyloid-beta deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-beta1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology, accelerated the deposition of amyloid-beta peptide. More TGF-beta1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-beta deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-beta1 may initiate or promote amyloidogenesis in Alzheimer's disease and in experimental models and so may be a risk factor for developing Alzheimer's disease.

    View details for Web of Science ID A1997YA00800060

    View details for PubMedID 9335500

  • Astroglial overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice JOURNAL OF NEUROIMMUNOLOGY WYSSCORAY, T., Borrow, P., Brooker, M. J., Mucke, L. 1997; 77 (1): 45-50


    Cerebral expression of the injury response cytokine transforming growth factor-beta 1 (TGF-beta 1) has been found to be increased in several neurological diseases but it remains unclear whether its function is primarily beneficial or detrimental. Here we show that transgenic (tg) mice that overexpress bioactive (TGF-beta 1 in the central nervous system (CNS) and show no overt phenotype in the unmanipulated state, are more susceptible to the immune-mediated CNS disease experimental autoimmune encephalomyelitis (EAE). TGF-beta 1 tg mice with EAE showed an earlier onset of clinical symptoms, more severe disease and increased mononuclear cell infiltration in their spinal cords compared with non-tg littermate controls with EAE. Whereas previous observations indicated that increased peripheral levels of TGF-beta 1 can suppress EAE, our findings demonstrate that local expression of TGF-beta 1 within the CNS parenchyma can enhance immune cell infiltration and intensify the CNS impairment resulting from peripherally triggered autoimmune responses.

    View details for Web of Science ID A1997XG79200006

    View details for PubMedID 9209267

  • Cellular signaling roles of TGF beta, TNF alpha and beta APP in brain injury responses and Alzheimer's disease BRAIN RESEARCH REVIEWS Mattson, M. P., Barger, S. W., Furukawa, K., Bruce, A. J., WYSSCORAY, T., Mark, R. J., Mucke, L. 1997; 23 (1-2): 47-61


    beta-Amyloid precursor protein (beta APP), transforming growth factor beta (TGF beta), and tumor necrosis factor-alpha (TNF alpha) are remarkably pleiotropic neural cytokines/neurotrophic factors that orchestrate intricate injury-related cellular and molecular interactions. The links between these three factors include: their responses to injury; their interactive effects on astrocytes, microglia and neurons; their ability to induce cytoprotective responses in neurons; and their association with cytopathological alterations in Alzheimer's disease. Astrocytes and microglia each produce and respond to TGF beta and TNF alpha in characteristic ways when the brain is injured. TGF beta, TNF alpha and secreted forms of beta APP (sAPP) can protect neurons against excitotoxic, metabolic and oxidative insults and may thereby serve neuroprotective roles. On the other hand, under certain conditions TNF alpha and the fibrillogenic amyloid beta-peptide (A beta) derivative of beta APP can promote damage of neuronal and glial cells, and may play roles in neurodegenerative disorders. Studies of genetically manipulated mice in which TGF beta, TNF alpha or beta APP ligand or receptor levels are altered suggest important roles for each factor in cellular responses to brain injury and indicate that mediators of neural injury responses also have the potential to enhance amyloidogenesis and/or to interfere with neuroregeneration if expressed at abnormal levels or modified by strategic point mutations. Recent studies have elucidated signal transduction pathways of TGF beta (serine/threonine kinase cascades), TNF alpha (p55 receptor linked to a sphingomyelin-ceramide-NF kappa B pathway), and secreted forms of beta APP (sAPP; receptor guanylate cyclase-cGMP-cGMP-dependent kinase-K+ channel activation). Knowledge of these signaling pathways is revealing novel molecular targets on which to focus neuroprotective therapeutic strategies in disorders ranging from stroke to Alzheimer's disease.

    View details for Web of Science ID A1997WN18500003

    View details for PubMedID 9063586

  • Dysregulation of signal transduction pathways as a potential mechanism of nervous system alterations in HIV-1 gp 120 transgenic mice and humans with HIV-1 encephalitis JOURNAL OF CLINICAL INVESTIGATION WYSSCORAY, T., Masliah, E., Toggas, S. M., Rockenstein, E. M., Brooker, M. J., Lee, H. S., Mucke, L. 1996; 97 (3): 789-798


    HIV-1 associated central nervous system (CNS) disease involves neuronal damage and prominent reactive astrocytosis, the latter characterized by strong upregulation of the glial fibrillary acidic protein (GFAP) in astrocytes. Similar alterations are found in transgenic mice expressing the HIV-1 envelope protein gp120 in the CNS. Because alterations of astrocyte functions could contribute to neuronal impairment, we compared brains of gp120 transgenic mice and gp120-transfected C6 astrocytoma cells with controls and found that gp120 induced a prominent elevation of steady state GFAP mRNA levels, primarily due to transcript stabilization. Increased levels of GFAP mRNA were also found in nontransfected C6 cells exposed to recombinant gp120. Exposure of C6 cells or primary mouse astrocytes to soluble gp120 led to activation of PKC as indicated by redistribution and increase in PKC immunoreactivity at the single cell level. gp120 effects were diminished by inhibitors of protein kinase C (PKC) but not inhibitors of protein kinase A. PKC activity was upmodulated in gp120-transfected C6 cells and in the CNS of gp120 transgenic mice. Further, brain tissue from patients with HIV-1 encephalitis and from gp120 transgenic mice showed increased PKC immunoreactivity. Taken together, these results indicate that gp120-induced increases in PKC activity may contribute to the gliosis seen in gp120 transgenic mice as well as in HIV-1-infected humans and raise the question of whether dysregulation of signal transduction pathways represents a general mechanism of HIV-associated pathogenesis.

    View details for Web of Science ID A1996UB65600028

    View details for PubMedID 8609236



    The synthesis of IgE is regulated by cytokines secreted from T-helper cells. The studies on cytokine secretion by peripheral blood mononuclear cells (PBMC) upon stimulation with antigen or allergen are difficult due to low levels of cytokines, especially of interleukin-4 (IL-4).In this study we tried to establish a culture system, which could enable the measurement of the cytokine profiles in specifically activated cultures.Three methods to potentiate cytokine secretion were evaluated: PBMC from bee venom or house dust mite (Dermatophagoides pteronyssinus) allergic patients as well as normal subjects were stimulated either with the major bee venom allergen phospholipase A2 (PLA) or with the major D. pteronyssinus allergen (Der p 1) or with the control antigens tetanus toxoid (TT) and purified protein derivate (PPD). After 7 days of culture the cells were restimulated either with plastic bound OKT3 F(ab)2 monoclonal antibodies (MoAbs), with the appropriate antigen + antigen presenting cells or with IL-2. The secretion of cytokines (IL-4, IFN gamma) was measured after restimulation of the cultures (day 8).While OKT3 F(ab)2 was unable to activate resting T cells, it could restimulate preactivated cells. Restimulation with OKT3 F(ab)2 induced higher IL-4 and IFN gamma secretion than restimulation with IL-2 or antigen. TT and PLA stimulated a similar cytokine secretion profile in normal and PLA allergic subjects with substantial levels of both IL-4 and IFN gamma. In contrast, PPD induced virtually only IFN gamma secretion. Der p 1 stimulated mainly IL-4 secretion but also IFN gamma production in some mite allergic patients.We have established a cell culture system, which combines antigen specificity with a strong cytokine inducing signal provided by anti-CD3 MoAbs. TH-1 and TH-2 characteristic cytokine patterns can be observed in short-term PBMC cultures already after 8 days of culture.

    View details for Web of Science ID A1995TE20600013

    View details for PubMedID 8581844



    The development of cytotoxic CD4+ T lymphocytes that can kill target cells in a MHC class II-restricted manner was evaluated by comparing different APCs. B-lymphoblasts (B-LCL) pulsed with the superantigen staphylococcus enterotoxin B or allogeneic B-lymphoblasts induce CD4+ T cells without cytotoxic activity. In contrast, superantigen-pulsed, MHC class II+ T cell blasts or allogeneic T cell blasts preferentially induce the development of specific, MHC class II-restricted CD4+ cytotoxic effector cells. CD4+ T cell clones generated with T or B cell blasts as APCs (T- or B-APCs) differ in their cytolytic potential, but secrete a similar cytokine pattern. Our data implicate that activated T-APCs preferentially induce a cytotoxic, CD8+ and CD4+ T cell response. Because the density of CD80 expression is lower on activated T-APCs than on B-APCs, we studied the involvement of CD28 and CD80 adhesion molecules in the generation of CD4+ CTLs. Partial blockade of the CD80 molecule with a CTLA4-Ig fusion protein and with specific anti-CD80 mAbs on B-APCs enhanced the generation of CD4+ CTLs. Specific anti-CD86 mAbs, on the contrary, had no effect on the generation of CD4+ CTLs. In contrast, stimulation of CD28, the CD80 counter-receptor, with a cross-linked B7-Ig fusion protein or with an anti-CD28 mAb, inhibited the generation of CD4+ CTLs. Thus, a reduced interaction between CD80 and CD28 may be relevant for the induction of CD4+ CTLs. This shows a new and not yet described function of these adhesion molecules. This induction of a cytotoxic immune response by T cells as APCs may be relevant for the anticlonotypic regulation of T cells and for the depletion of CD4+ T cells in HIV infection.

    View details for Web of Science ID A1995RE57400015

    View details for PubMedID 7541409



    A number of important neurological diseases, including HIV-1 encephalitis, Alzheimer's disease, and brain trauma, are associated with increased cerebral expression of the multifunctional cytokine transforming growth factor-beta 1 (TGF-beta 1). To determine whether overexpression of TGF-beta 1 within the central nervous system (CNS) can contribute to the development of neuropathological alterations, a bioactive form of TGF-beta 1 was expressed in astrocytes of transgenic mice. Transgenic mice with high levels of cerebral TGF-beta 1 expression developed a severe communicating hydrocephalus, seizures, motor incoordination, and early runting. While unmanipulated heterozygous transgenic mice from a low expressor line showed no such alterations, increasing TGF-beta 1 expression in this line by injury-induced astroglial activation or generation of homozygous offspring did result in the abnormal phenotype. Notably, astroglial overexpression of TGF-beta 1 consistently induced a strong upmodulation of the extracellular matrix proteins laminin and fibronectin in the CNS, particularly in the vicinity of TGF-beta 1-expressing perivascular astrocytes, but was not associated with obvious CNS infiltration by hematogenous cells. While low levels of extracellular matrix protein expression may assist in CNS wound repair and regeneration, excessive extracellular matrix deposition could result in the development of hydrocephalus. As an effective inducer of extracellular matrix components, TGF-beta 1 may also contribute to the development of other neuropathological alterations, eg, the formation of amyloid plaques in Alzheimer's disease.

    View details for Web of Science ID A1995RH02300007

    View details for PubMedID 7604885



    Activated T-cells expressing MHC class II surface antigens are able to present antigen and thus function as peptide-presenting cells (T-APCs). In this study we investigated whether antigen presentation by T-cells induced programmed cell death. As a model we used tetanus p30 peptide (aa 947-967)-specific, noncytotoxic CD4+ T-cell clones (C11 and C31). For experimental purposes these T-cell clones were stimulated (a) with p30 peptide-pulsed and fixed EBV-transformed antigen-presenting cells (B-APCs), (b) with p30-pulsed and fixed activated T-cells as APCs (as T-APCs we used either the T-cell clones themselves or an autologous T-cell clone (CT3) with p30 unrelated specificity), or (c) with soluble p30 peptide. The efficiency of antigen presentation was monitored by measuring proliferation as [3H]thymidine uptake. Apoptosis was measured by quantifying fragmented, cytoplasm DNA with the fluorescent dye 4,6-diamidino-2-phenylindole or by visualizing fragmented DNA by gel electrophoresis. Stimulation with p30-pulsed and fixed B-APCs or T-APCs induced proliferation but no apoptosis of the responding T-cells. However, stimulation of cloned T-cells with soluble peptide induced up-regulation of the FAS surface molecules and apoptosis, which was dependent on the peptide doses. Because cloned T-cells express HLA class II molecules, they can theoretically exert both functions at once: antigen presentation and antigen response when they are stimulated with soluble peptide. Because death by apoptosis is only seen under such circumstances, we suggest that T-cells simultaneously presenting and responding to an antigen die of apoptosis and thus contribute to the down-regulation of the immune response. Such phenomena might occur in HIV infection when activated CD4+ T-cells take up gp120 via their CD4 molecules, present it on their HLA class II surface antigens, and are simultaneously stimulated via their TCR.

    View details for Web of Science ID A1995QK25200010

    View details for PubMedID 7532549



    T cells recognize peptides in association with major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APC). To sensitize APC for antigen presentation in vitro and in vivo, high concentrations of synthetic peptides can be added from the outside and bind to the MHC molecules, thereby mimicking naturally processed peptides. In this report we investigated whether the transferrin (Tf) molecule could be used as a carrier to introduce antigenic peptides into the antigen presentation pathway of APC. We coupled to Tf various MHC class II DR1 restricted peptides and compared the sensitization of DR1+ APC by the Tf-bound or by the soluble peptide, using peptide-specific T cell clones (TCC). The presentation of the Tf-bound peptides was MHC restricted and could be blocked by the fixation of the APC with glutaraldehyde or by the addition of an excess of Tf. Tf-bound peptides were more efficiently presented than soluble peptides, since smaller concentrations were required to sensitize APC. Moreover, they could compete with a soluble peptide for MHC restricted presentation with a very high efficiency if compared to soluble competing peptides. Tf peptide conjugates could even compete with the presentation of a native antigen like tetanus toxoid. Peptides bound to the transferrin molecule might be useful for immunization strategies, as the relevant bound peptides are efficiently presented to peptide-specific TCC.

    View details for Web of Science ID A1994PJ58700004

    View details for PubMedID 8087868



    In the anagen human hair follicle, the epithelial cells from the infrainfundibular portion and the hair matrix cells express markedly lower numbers of major histocompatibility complex class I molecules than interfollicular epidermal keratinocytes. During the catagen phase of the hair cycle, class I expression on these cells increases, and activated macrophages aggregate around the follicle, which has led to the hypothesis that the cells to be resorbed are recognized by virtue of their low class I antigen expression. In the present study, we showed that, in vitro, outer root sheath cells also maintain a lower constitutive expression of MHC class I molecules compared with epidermal keratinocytes. In contrast, other surface antigens such as HLA-DR, -DP and -DQ, ICAM-1, LFA-3 and CD29, which are all known to participate in leucocyte-keratinocyte interactions, were similarly expressed in both cell types. Furthermore, interferon gamma strongly upregulated MHC class I and II and ICAM-1 expression in both cell types, whereas CD29 and LFA-3 remained unaffected. Tumour necrosis factor alpha, to a lesser extent, also upregulated MHC class I and ICAM-1 expression, but not class II expression. The differences in constitutive surface antigen expression of infrainfundibular outer root sheath cells compared with interfollicular epidermal keratinocytes emphasizes a distinct role of this cell type in the hair cycle, and possibly also in alopecia areata.

    View details for Web of Science ID A1994PB73500005

    View details for PubMedID 7917981



    Human T cells express major histocompatibility complex (MHC) class II antigens and adhesion molecules characteristic of antigen-presenting cells (APCs), and recent in vitro and in vivo evidence supports an antigen-presenting function for T cells. In this guise, T cells provide downregulatory signals for the immune response by inducing anergy in T cells that have already been activated and cytotoxicity in resting T cells. Here, Werner Pichler and Tony Wyss-Coray suggest that this may represent an important negative mechanism for T-cell homeostasis.

    View details for Web of Science ID A1994NV21300005

    View details for PubMedID 7522009



    To simplify the screening of monoclonal antibodies to different human T cell surface molecules a live cell enzyme-linked immunosorbent assay (cell ELISA) has been established and optimized. The assay was performed in 96-well plates. By using living human T lymphocytes in suspension surface modification by fixation or insolubilization of the cells was avoided. Several parameters influencing sensitivity and specificity were studied. About 150 ng/ml of mouse monoclonal antibodies to cell surface antigens could be detected when using 5 x 10(4) cells per well and a 1/1000 dilution of the anti-mouse IgG-alkaline phosphatase conjugate. This sensitivity permitted the primary screening of cell specific antibodies from hybridoma supernatants. The same detection limit was obtained in flow cytometric analysis. If required, the sensitivity of the cell ELISA could be increased using higher cell numbers and conjugate concentration. When analysing different cell lines with selected antibodies the cell ELISA was found to be as sensitive and specific as the fluorescence assay. The assay was applied to the screening of supernatants from hybridomas developed against human T helper cell clones and the detection of V beta specificities of T cell clones.

    View details for Web of Science ID A1994NK46000011

    View details for PubMedID 8176241

  • Peptide-induced T cell clones: Specificity, MHC restriction, proliferation and cytokine pattern as a function of different stimulations 7th International Paul Ehrlich Seminar Pichler, W. J., Brander, C., Mauri, D., Frutig, K., WYSSCORAY, T. GUSTAV FISCHER VERLAG. 1994: 141–154


    CD4+ T cell clones were generated to tetanus toxin or to two tetanus toxin-derived peptides p2 (AA 830-834) and p30 (AA 947-976). 11 of the 24 p30-specific clones reacted to shorter p30 subunits (p301 or p302), and only 14 of the p2 or p30-specific clones reacted with TT presented by EBV-transformed B cell lines (B-LCL). The p30-specific clones were HLA-DP4 restricted. In contrast to autologous B cell lines, the majority of allogeneic, but HLA-DP4-positive cell lines failed to present p30 to the specific clones. We concluded that T cell clones are highly specific and that both, small alterations of the peptide length as well as discrete differences of the HLA-molecule may abrogate recognition of the peptide HLA complex by T cells. Moreover, use of peptides as stimulators of T cells may recruit and activate T cells which fail the "original" peptide, derived from normal antigen processing. Clones could usually be maintained in culture for 4-6 months, but with the help of freezing and thawing some clones are now available for over 2 years and still specific. Comparison of different autologous antigen-presenting cells, namely B-LCL and activated MHC class II-positive T cells revealed that not all clones were able to mount a proliferative response to peptide presentation by T cells, while all clones proliferated to B cells as APC. If stimulated with peptide and B-LCL, the clone proliferating to T cells as APC (so-called T responder clones) secreted a broad spectrum of cytokines (Th0-like) and were easier to maintain in culture. In contrast, clones which were unable to proliferate to peptide presentation, so-called T-nonresponder clones, showed a more restricted cytokine pattern and elevated or very low IL4/IFN gamma ratio upon antigen specific stimulation. However, all clones secreted at least small amounts of IL2, IL4, IFN gamma and TNF alpha, if stimulated by PMA and ionomycin. Thus, both chemical and antigen-specific stimulations should be considered if T cell clones are classified as Th1 or Th2, whereby those clones, which secrete a limited cytokine pattern after antigen stimulation only, might be named Th1 or Th2 like clones, while clones which even after PMA/ionomycin do not secrete all cytokines, might represent "real" Th1 or Th2 clones.

    View details for Web of Science ID A1994BD88X00012

    View details for PubMedID 7873053



    One of the factors that may influence the cytokine secretion profile of a T cell is the antigen-presenting cell (APC). Since activated human T cells have been described to express major histocompatibility complex (MHC) class II molecules as well as costimulatory molecules for T cell activation, like e.g. ICAM-1, LFA-3 and B7, they might play a role as APC and be involved in the regulation of T-Tcell interactions. To define further the role of T cells as APC we tested their capacity to induce proliferation and cytokine production in peptide- or allospecific T cell clones and compared it with conventional APC, like B lymphoblasts (B-LCL) or HTLV-1-transformed T cells, or with non-classical APC, like activated keratinocytes or eosinophils. CD4+, DP-restricted T cell clones specific for a tetanus toxin peptide (amino acids 947-967) and CD4+, DR-restricted allospecific T cell clones produced interleukin (IL)-2, IL-4, tumor necrosis factor-alpha and interferon-gamma (IFN-gamma) after phorbol 12-myristate 13-acetate and ionomycin stimulation and a more restricted cytokine pattern after antigen stimulation. Dose-response curves revealed that the antigen-presenting capacity of activated, MHC class II+, B7+ T cells was comparable to the one of B-LCL. Both APC induced the same cytokine profile in the T cell clones despite a weaker proliferative response with T cells as APC. Suboptimal stimulations resulted in a lower IFN-gamma/IL-4 ratio. Cytokine-treated, MHC class II+ keratinocytes and eosinophils differed in the expression of adhesion molecules and their capacity to restimulate T cell clones. The strongly ICAM-1-positive keratinocytes induced rather high cytokine levels. In contrast, eosinophils, which express only low densities of MHC class II and no or only low levels of adhesion molecules (B7, ICAM-1 and LFA3), provided a reduced signal resulting in a diminished IFN-gamma/IL-4 ratio. We conclude that non-classical APC differ in their capacity to restimulate T cell clones, whereby the intensity of MHC class II and adhesion molecules (B7, ICAM-1) expressed seems to determine the efficacy of this presentation.

    View details for Web of Science ID A1993MM68900042

    View details for PubMedID 7504995



    Antigenic peptides derived from endogenous or viral proteins can associate with class I or class II major histocompatibility complex (MHC) molecules, while exogenous antigens are endocytosed, processed intracellularly and presented on MHC class II molecules. Here we describe a method that allows the presentation of an MHC class I-restricted antigenic peptide on MHC class I molecules, although it was taken up from the outside. The HLA-A2-restricted influenza virus matrix protein-derived peptide (flu, 57-68) was used either in soluble form or coupled via an S-S bridge to transferrin (Tf-flu). Target cells were incubated with flu or Tf-flu and the effective antigen presentation was detected in a cytotoxicity assay using flu peptide-specific, HLA-A2-restricted CD8+ cytotoxic T lymphocytes. Sensitization of target cells with Tf-flu required 5 to 10 times higher molar concentrations of peptide compared to sensitization with soluble free peptide. The Tf-flu construct was taken up by the cells via the Tf receptor (CD71) as the binding of Tf-flu was blocked by an excess of Tf. In contrast to the flu peptide, cytotoxicity elicited by Tf-flu was blocked by brefeldin A but not by chloroquine nor inhibitors of intracellular reducing steps, like 1-buthionine-(s,r)-sulfoximine or n-ethylmaleimide. Presentation of the flu peptide derived from Tf-flu construct is not hindered in the mutant T2 cell line, which lacks genes coding for transporter proteins for antigenic peptides (TAP1/TAP2) and proteasomes subunits, suggesting that the processing pathway described in this report may involve TAP-independent steps.

    View details for Web of Science ID A1993MM68900025

    View details for PubMedID 8258336



    The B cell antigen B7 delivers a strong co-stimulatory signal for the activation of T cells by binding to its ligands CD28 and CTLA4. Here we demonstrate the surface expression of the B7 molecule on activated human T cells in vitro and under certain conditions in vivo and its functional importance in T-T cell interactions. B7 was detected by flow cytometry on antigen-specific CD4+ and allospecific CD8+ cloned T cells from different donors with anti-B7 monoclonal antibody (mAb) or a soluble CTLA4-C gamma 1 chimera molecule and by reverse transcription-polymerase chain reactions. The expression of B7 was up-regulated following restimulation of the T cell clones and peaked after 7-9 days. Moreover, we show that the B7 molecule on T cells is functionally involved in T-T cell interactions: mAb to CD28 and the CTLA4-Ig fusion protein could inhibit the proliferation of specific T cell clones in response to T cells as antigen-presenting cells (APC) or the proliferation of peripheral blood mononuclear cells in a primary allostimulation with activated T cells as stimulator cells. Finally, we found that B7 can be expressed on freshly isolated circulating T cells since in a preliminary study with a limited number of patients, B7 was present on a subset of CD3+ cells. B7 was expressed on activated T cells (CD4+ and CD8+) of certain human immunodeficiency virus (HIV)-infected individuals (0.5-20% B7+CD8+ cells) or some patients with autoimmune diseases whereas CD3+ cells of healthy individuals did not express B7. The coexpression of major histocompatibility complex class II molecules and B7 may be relevant for the capacity of activated T cells to function as APC. The expression of B7 on T cells in vivo in autoimmune diseases and in HIV infection may be important for a better understanding of these diseases.

    View details for Web of Science ID A1993LY55500018

    View details for PubMedID 7690323



    In this report, we describe the discrimination of human T cell clones based on their reactivity with activated T cells as antigen-presenting cells (APC). CD4+ T cell clones specific for peptide P30 of tetanus toxin (amino acids 947-967) and restricted to the DP4 molecule were established and tested for proliferation to peptide presented either by peripheral blood mononuclear cells (PBMC), Epstein-Barr virus (EBV)-transformed B cells or major histocompatibility complex (MHC) class II-expressing T cells. We found two sets of T cell clones: one set proliferated to peptide presentation by PBMC, EBV-transformed B cell lines (EBV-B cells) and MHC class II+ T cells (termed T-responder clones), while the other set of clones was only stimulated to proliferate, if the peptide was presented by PBMC or EBV-B cells, but not by T cells (T-nonresponder clones). Nevertheless, these T-nonresponder clones recognized P30 also on T cells, as revealed by Ca2+ influx. The discrimination of the clones was not due to different avidities of the T cell receptors (TcR) of individual clones for the MHC-peptide complex as T-responder and T-nonresponder clones had similar dose-response curves to P30 presented by fixed EBV-B cell lines. Addition of cytokines [interleukin (IL)-1, IL-2, IL-4 and interferon gamma] did not change the proliferative response of the clones, which was consistent throughout an observation period of greater than 4 months. T-nonresponder clones, exposed to P30 on MHC class II-expressing T cells, became not anergic, as they could be restimulated by P30 presented on EBV-B cells. The measurement of a panel of T cell activation markers and adhesion molecules on T-responder and T-nonresponder clones revealed a higher expression of the CD28 molecule on the T-nonresponder clones. The data suggest that freshly cloned T cells can be differentiated by peptide presentation on classical (PBMC, EBV-B cells) or non-classical APC (class II+ T cells), and that this discrimination is further underlined by different levels of adhesion molecules.

    View details for Web of Science ID A1992JN49000017

    View details for PubMedID 1381313



    Human T cells can express MHC-class II products and were shown to be potential antigen-presenting cells. However, they are unable to capture the antigen and only antigens, which bind to T cell membranes such as the gp120 glycoprotein of HIV, are internalized, processed, and presented by T cells. To better understand the role of T cells as antigen-presenting cells, we established a method which overcomes the lack of antigen capture by T cells. Antigen (tetanus toxoid, TT) or an antigenic peptide of TT (residue 830-843, P2) was coupled to antibodies directed to T cell surface molecules such as CD2, CD4, CD8. Antibody/TT and antibody/P2 constructs stimulated P2-specific T cell clones in the absence of accessory cells, if the antibody recognized a T cell surface structure. Compared to the peptide alone, a 100-500 times lower molar concentration of the antibody/peptide construct was required to achieve a similar proliferative response. T cell stimulation via the constructs involved intracellular processing, as nonspecific, glutaraldehyde fixed T cell lines pulsed with the constructs could present the peptide and processing inhibitors like Leupeptin or Chloroquine inhibited the development of a proliferative response to the constructs. Our data underline the ability of T cells to function as antigen-processing and -presenting cells and show that antibody/antigen or antibody/peptide constructs are able to direct a certain antigen or peptide to a T cell. Antibody/peptide constructs may be interesting tools to better understand antigen processing and to study the consequences of antigen presentation by different cells.

    View details for Web of Science ID A1992GW21300025

    View details for PubMedID 1728968