Shamloo Lab Publications

Publications

  • Role of Endoplasmic Reticulum Stress in Learning and Memory Impairment and Alzheimer's Disease-Like Neuropathology in the PS19 and APP(Swe) Mouse Models of Tauopathy and Amyloidosis. eNeuro Briggs, D. I., Defensor, E. n., Memar Ardestani, P. n., Yi, B. n., Halpain, M. n., Seabrook, G. n., Shamloo, M. n. ; 4 (4)

    Abstract

    Emerging evidence suggests that endoplasmic reticulum (ER) stress may be involved in the pathogenesis of Alzheimer's disease (AD). Recently, pharmacological modulation of the eukaryotic translation initiation factor-2 (eIF2α) pathway was achieved using an integrated stress response inhibitor (ISRIB). While members of this signaling cascade have been suggested as potential therapeutic targets for neurodegeneration, the biological significance of this pathway has not been comprehensively assessed in animal models of AD. The present study investigated the ER stress pathway and its long-term modulation utilizing in vitro and in vivo experimental models of tauopathy (MAPT P301S)PS19 and amyloidosis (APP(Swe)). We report that thapsigargin induces activating transcription factor-4 (ATF4) in primary cortical neurons (PCNs) derived from rat and APP(Swe) nontransgenic (nTg) and transgenic (Tg) mice. ISRIB mitigated the induction of ATF4 in PCNs generated from wild-type (WT) but not APP(Swe) mice despite partially restoring thapsigargin-induced translational repression in nTg PCNs. In vivo, C57BL/6J and PS19 mice received prolonged, once-daily administration of ISRIB. While the compound was well tolerated by PS19 and C57BL/6J mice, APP(Swe) mice treated per this schedule displayed significant mortality. Thus, the dose was reduced and administered only on behavioral test days. ISRIB did not improve learning and memory function in APP(Swe) Tg mice. While ISRIB did not reduce tau-related neuropathology in PS19 Tg mice, no evidence of ER stress-related dysfunction was observed in either of these Tg models. Taken together, the significance of ER stress and the relevance of these models to the etiology of AD require further investigation.

    View details for PubMedID 28721361

    View details for PubMedCentralID PMC5510086

  • Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease. Neurobiology of disease Evans, A. K., Ardestani, P. n., Yi, B. n., Park, H. H., Lam, R. n., Shamloo, M. n. 2020: 105089

    Abstract

    Adrenergic systems regulate both cognitive function and immune function. The primary source of adrenergic signaling in the brain is norepinephrine (NE) neurons of the locus coeruleus (LC), which are vulnerable to age-related degeneration and are one of the earliest sites of pathology and degeneration in neurodegenerative disorders such as Alzheimer's Disease (AD). Loss of adrenergic tone may potentiate neuroinflammation both in aging and neurodegenerative conditions. Importantly, beta-blockers (beta-adrenergic antagonists) are a common treatment for hypertension, co-morbid with aging, and may further exacerbate neuroinflammation associated with loss of adrenergic tone in the central nervous system (CNS). The present studies were designed to both examine proinflammatory consequences of beta-blocker administration in an acute lipopolysaccharide (LPS) model as well as to examine chronic effects of beta-blocker administration on neuroinflammation and behavior in an amyloid-beta protein precursor (APP) mouse model of AD. We provide evidence for robust potentiation of peripheral inflammation with 4 different beta-blockers in an acute model of LPS. However, beta-blockers did not potentiate CNS inflammation in this model. Notably, in this same model, the genetic knockdown of either beta1- or beta2-adrenergic receptors in microglia did potentiate CNS inflammation. Furthermore, in an APP mouse model of amyloid pathology, chronic beta-blocker administration did potentiate CNS inflammation. The beta-blocker, metoprolol, also induced markers of phagocytosis and impaired cognitive behavior in both wild-type and APP mice. Given the induction of markers of phagocytosis in vivo, we examined phagocytosis of synaptosomes in an in vitro primary microglia culture and showed that beta-blockers enhanced whereas beta-adrenergic agonists inhibited phagocytosis of synaptosomes. In conclusion, beta-blockers potentiated inflammation peripherally in a systemic model of inflammation and centrally in an amyloidosis model of neuroinflammation. Additionally, beta-blockers impaired learning and memory and modulated synaptic phagocytosis with implications for synaptic degeneration. These findings warrant further consideration of the proinflammatory consequences of chronic beta-blocker administration, which are not restricted to the periphery in patients with neurodegenerative disorders.

    View details for DOI 10.1016/j.nbd.2020.105089

    View details for PubMedID 32971233

  • Reactions to Multiple Ascending Doses of the Microtubule Stabilizer TPI-287 in Patients With Alzheimer Disease, Progressive Supranuclear Palsy, and Corticobasal Syndrome: A Randomized Clinical Trial. JAMA neurology Tsai, R. M., Miller, Z., Koestler, M., Rojas, J. C., Ljubenkov, P. A., Rosen, H. J., Rabinovici, G. D., Fagan, A. M., Cobigo, Y., Brown, J. A., Jung, J. I., Hare, E., Geldmacher, D. S., Natelson-Love, M., McKinley, E. C., Luong, P. N., Chuu, E. L., Powers, R., Mumford, P., Wolf, A., Wang, P., Shamloo, M., Miller, B. L., Roberson, E. D., Boxer, A. L. 2019

    Abstract

    Importance: Basket-design clinical trials that allow investigation of treatment effects on different clinical syndromes that share the same molecular pathophysiology have not previously been attempted in neurodegenerative disease.Objective: To assess the safety, tolerability, and pharmacodynamics of the microtubule stabilizer TPI-287 (abeotaxane) in Alzheimer disease (AD) or the 4-repeat tauopathies (4RT) progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).Design, Setting, and Participants: Two parallel-design, double-blind, placebo-controlled phase 1 randomized clinical trials in AD and 4RT were conducted from December 20, 2013, through May 4, 2017, at the University of California, San Francisco, and University of Alabama at Birmingham. A total of 94 patients with clinically diagnosed AD (n=39) and 4RT (n=55) were screened; of these, 3 refused to participate, and 10 with AD and 11 with 4RT did not meet inclusion criteria. A total of 29 patients with AD, 14 with PSP, and 30 with beta-amyloid-negative CBS (determined on positron emission tomography findings) were enrolled. Data were analyzed from December 20, 2013, through May 4, 2017, based on modified intention to treat.Interventions: Randomization was 8:3 drug to placebo in 3 sequential dose cohorts receiving 2.0, 6.3, or 20.0 mg/m2 of intravenous TPI-287 once every 3 weeks for 9 weeks, with an optional 6-week open-label extension.Main Outcomes and Measures: Primary end points were safety and tolerability (maximal tolerated dose) of TPI-287. Secondary and exploratory end points included TPI-287 levels in cerebrospinal fluid (CSF) and changes on biomarker, clinical, and neuropsychology measures.Results: A total of 68 participants (38 men [56%]; median age, 65 [range, 50-85] years) were included in the modified intention-to-treat analysis, of whom 26 had AD (14 women [54%]; median age, 63 [range, 50-76] years), and 42 had 4RT (16 women [38%]; median age, 69 [range, 54-83] years). Three severe anaphylactoid reactions occurred in TPI-287-treated patients with AD, whereas none were seen in patients with 4RT, leading to a maximal tolerated dose of 6.3 mg/m2 for AD and 20.0 mg/m2 for 4RT. More falls (3 in the placebo group vs 11 in the TPI-287 group) and a dose-related worsening of dementia symptoms (mean [SD] in the CDR plus NACC FTLD-SB [Clinical Dementia Rating scale sum of boxes with frontotemporal dementia measures], 0.5 [1.8] in the placebo group vs 0.7 [1.6] in the TPI-287 group; median difference, 1.5 [95% CI, 0-2.5]; P=.03) were seen in patients with 4RT. Despite undetectable TPI-287 levels in CSF, CSF biomarkers demonstrated decreased chitinase-3-like protein-1 (YKL-40) levels in the 4RT treatment arm (mean [SD], -8.4[26.0] ng/mL) compared with placebo (mean [SD], 10.4[42.3] ng/mL; median difference, -14.6 [95% CI, -30.0 to 0.2] ng/mL; P=.048, Mann-Whitney test).Conclusions and Relevance: In this randomized clinical trial, TPI-287 was less tolerated in patients with AD than in those with 4RT owing to the presence of anaphylactoid reactions. The ability to reveal different tau therapeutic effects in various tauopathy syndromes suggests that basket trials are a valuable approach to tau therapeutic early clinical development.Trial Registration: ClinicalTrials.gov identifiers: NCT019666666 and NCT02133846.

    View details for DOI 10.1001/jamaneurol.2019.3812

    View details for PubMedID 31710340

  • Activity-dependent modulation of hippocampal synaptic plasticity via PirB and endocannabinoids MOLECULAR PSYCHIATRY Djurisic, M., Brott, B. K., Saw, N. L., Shamloo, M., Shatz, C. J. 2019; 24 (8): 1206–19
  • LRRK2 modifies alpha-syn pathology and spread in mouse models and human neurons ACTA NEUROPATHOLOGICA Bieri, G., Brahic, M., Bousset, L., Couthouis, J., Kramer, N. J., Ma, R., Nakayama, L., Monbureau, M., Defensor, E., Schuele, B., Shamloo, M., Melki, R., Gitler, A. D. 2019; 137 (6): 961–80
  • PGE(2) signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Liu, Q., Liang, X., Wang, Q., Wilson, E. N., Lam, R., Wang, J., Kong, W., Tsai, C., Pan, T., Larkin, P. B., Shamloo, M., Andreasson, K. I. 2019; 116 (20): 10019–24
  • LRRK2 modifies alpha-syn pathology and spread in mouse models and human neurons. Acta neuropathologica Bieri, G., Brahic, M., Bousset, L., Couthouis, J., Kramer, N. J., Ma, R., Nakayama, L., Monbureau, M., Defensor, E., Schule, B., Shamloo, M., Melki, R., Gitler, A. D. 2019

    Abstract

    Progressive aggregation of the protein alpha-synuclein (alpha-syn) and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are key histopathological hallmarks of Parkinson's disease (PD). Accruing evidence suggests that alpha-syn pathology can propagate through neuronal circuits in the brain, contributing to the progressive nature of the disease. Thus, it is therapeutically pertinent to identify modifiers of alpha-syn transmission and aggregation as potential targets to slow down disease progression. A growing number of genetic mutations and risk factors has been identified in studies of familial and sporadic forms of PD. However, how these genes affect alpha-syn aggregation and pathological transmission, and whether they can be targeted for therapeutic interventions, remains unclear. We performed a targeted genetic screen of risk genes associated with PD and parkinsonism for modifiers of alpha-syn aggregation, using an alpha-syn preformed-fibril (PFF) induction assay. We found that decreased expression of Lrrk2 and Gba modulated alpha-syn aggregation in mouse primary neurons. Conversely, alpha-syn aggregation increased in primary neurons from mice expressing the PD-linked LRRK2 G2019S mutation. In vivo, using LRRK2 G2019S transgenic mice, we observed acceleration of alpha-syn aggregation and degeneration of dopaminergic neurons in the SNpc, exacerbated degeneration-associated neuroinflammation and behavioral deficits. To validate our findings in a human context, we established a novel human alpha-syn transmission model using induced pluripotent stem cell (iPS)-derived neurons (iNs), where human alpha-syn PFFs triggered aggregation of endogenous alpha-syn in a time-dependent manner. In PD subject-derived iNs, the G2019S mutation enhanced alpha-syn aggregation, whereas loss of LRRK2 decreased aggregation. Collectively, these findings establish a strong interaction between the PD risk gene LRRK2 and alpha-syn transmission across mouse and human models. Since clinical trials of LRRK2 inhibitors in PD are currently underway, our findings raise the possibility that these may be effective in PD broadly, beyond cases caused by LRRK2 mutations.

    View details for PubMedID 30927072

  • Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity Nature Immunology Liu, Q., Johnson, E., et al 2019
  • PGE2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia. Proceedings of the National Academy of Sciences of the United States of America Liu, Q. n., Liang, X. n., Wang, Q. n., Wilson, E. N., Lam, R. n., Wang, J. n., Kong, W. n., Tsai, C. n., Pan, T. n., Larkin, P. B., Shamloo, M. n., Andreasson, K. I. 2019

    Abstract

    The inflammatory prostaglandin E2 (PGE2) EP2 receptor is a master suppressor of beneficial microglial function, and myeloid EP2 signaling ablation reduces pathology in models of inflammatory neurodegeneration. Here, we investigated the role of PGE2 EP2 signaling in a model of stroke in which the initial cerebral ischemic event is followed by an extended poststroke inflammatory response. Myeloid lineage cell-specific EP2 knockdown in Cd11bCre;EP2lox/lox mice attenuated brain infiltration of Cd11b+CD45hi macrophages and CD45+Ly6Ghi neutrophils, indicating that inflammatory EP2 signaling participates in the poststroke immune response. Inducible global deletion of the EP2 receptor in adult ROSA26-CreERT2 (ROSACreER);EP2lox/lox mice also reduced brain myeloid cell trafficking but additionally reduced stroke severity, suggesting that nonimmune EP2 receptor-expressing cell types contribute to cerebral injury. EP2 receptor expression was highly induced in neurons in the ischemic hemisphere, and postnatal deletion of the neuronal EP2 receptor in Thy1Cre;EP2lox/lox mice reduced cerebral ischemic injury. These findings diverge from previous studies of congenitally null EP2 receptor mice where a global deletion increases cerebral ischemic injury. Moreover, ROSACreER;EP2lox/lox mice, unlike EP2-/- mice, exhibited normal learning and memory, suggesting a confounding effect from congenital EP2 receptor deletion. Taken together with a precedent that inhibition of EP2 signaling is protective in inflammatory neurodegeneration, these data lend support to translational approaches targeting the EP2 receptor to reduce inflammation and neuronal injury that occur after stroke.

    View details for PubMedID 31036664

  • Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem (R)-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Ravina, K., Briggs, D. I., Kislal, S., Warraich, Z., Nguyen, T., Lam, R. K., Zarembinski, T. I., Shamloo, M. 2018; 19 (12)
  • Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith-Magenis syndrome PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Huang, W., Wang, D. C., Allen, W. E., Klope, M., Hu, H., Shamloo, M., Luo, L. 2018; 115 (42): 10744–49
  • Interaction of mitochondria fission factor with dynamin related protein 1 governs physiological mitochondria function in vivo SCIENTIFIC REPORTS Kornfeld, O. S., Qvit, N., Haileselassie, B., Shamloo, M., Bernardi, P., Mochly-Rosen, D. 2018; 8
  • Activity-dependent modulation of hippocampal synaptic plasticity via PirB and endocannabinoids. Molecular psychiatry Djurisic, M. n., Brott, B. K., Saw, N. L., Shamloo, M. n., Shatz, C. J. 2018

    Abstract

    The threshold for Hebbian synaptic plasticity in the CNS is modulated by prior synaptic activity. At adult CA3-CA1 synapses, endocannabinoids play a role in this process, but how activity engages and maintains this retrograde signaling system is not well understood. Here we show that conditional deletion of Paired Immunoglobulin-like receptor B (PirB) from pyramidal neurons in adult mouse hippocampus results in deficient LTD at CA3-CA1 synapses over a range of stimulation frequencies, accompanied by an increase in LTP. This finding can be fully explained by the disengagement of retrograde endocannabinoid signaling selectively at excitatory synapses. In the absence of PirB, the NMDAR-dependent regulation of endocannabinoid signaling is lost, while CB1R-dependent and group I mGluR-dependent regulation are intact. Moreover, mEPSC frequency in mutant CA1 pyramidal cells is elevated, consistent with a higher density of excitatory synapses and altered synapse pruning. Mice lacking PirB also perform better than WT in learning and memory tasks. These observations suggest that PirB is an integral part of an NMDA receptor-mediated synaptic mechanism that maintains bidirectional Hebbian plasticity and learning via activity-dependent endocannabinoid signaling.

    View details for PubMedID 29670176

  • Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO molecular medicine Joshi, A. U., Saw, N. L., Vogel, H. n., Cunnigham, A. D., Shamloo, M. n., Mochly-Rosen, D. n. 2018

    Abstract

    Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial dysfunction associated with excessive mitochondrial fission and fragmentation, which is predominantly mediated by Drp1 hyperactivation. Here, we determined whether inhibition of excessive fission by inhibiting Drp1/Fis1 interaction affects disease progression. We observed mitochondrial excessive fragmentation and dysfunction in several familial forms of ALS patient-derived fibroblasts as well as in cultured motor neurons expressing SOD1 mutant. In both cell models, inhibition of Drp1/Fis1 interaction by a selective peptide inhibitor, P110, led to a significant reduction in reactive oxygen species levels, and to improvement in mitochondrial structure and functions. Sustained treatment of mice expressing G93A SOD1 mutation with P110, beginning at the onset of disease symptoms at day 90, produced an improvement in motor performance and survival, suggesting that Drp1 hyperactivation may be an attractive target in the treatment of ALS patients.

    View details for PubMedID 29335339

  • Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer's disease. Oncotarget Joshi, A. U., Saw, N. L., Shamloo, M. n., Mochly-Rosen, D. n. 2018; 9 (5): 6128–43

    Abstract

    Mitochondrial dynamics, involving a balance between fusion and fission, regulates mitochondrial quality and number. Increasing evidence suggests that dysfunctional mitochondria play a role in Alzheimer's disease (AD). We observed that Drp1 interaction with one of the adaptors, Fis1, is significantly increased in Aβ-treated neurons and AD patient-derived fibroblasts. P110, a seven-amino acid peptide, which specifically inhibits Drp1/Fis1 interaction without affecting the interaction of Drp1 with its other adaptors, attenuated Aβ42-induced mitochondrial recruitment of Drp1 and prevented mitochondrial structural and functional dysfunction in cultured neurons, in cells expressing mutant amyloid precursor protein (KM670/671NL), and in five different AD patient-derived fibroblasts. Importantly, sustained P110 treatment significantly improved behavioral deficits, and reduced Aβ accumulation, energetic failure and oxidative stress in the brain of the AD mouse model, 5XFAD. This suggests that Drp1/Fis1 interaction and excessive mitochondrial fission greatly contribute to Aβ-mediated and AD-related neuropathology and cognitive decline. Therefore, inhibiting excessive Drp1/Fis1-mediated mitochondrial fission may benefit AD patients.

    View details for PubMedID 29464060

  • Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease. Journal of neurochemistry Yi, B., Sahn, J. J., Ardestani, P. M., Evans, A. K., Scott, L. L., Chan, J. Z., Iyer, S., Crisp, A., Zuniga, G., Pierce, J. T., Martin, S. F., Shamloo, M. 2017; 140 (4): 561-575

    Abstract

    Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases. Herein, we report the identification of a novel class of Sig2R binding ligands and their cellular and in vivo activity in experimental models of Alzheimer's disease (AD). We report that SAS-0132 and DKR-1051, selective ligands of Sig2R, modulate intracellular Ca(2+) levels in human SK-N-SH neuroblastoma cells. The Sig2R antagonists SAS-0132 and JVW-1009 are neuroprotective in a C. elegans model of amyloid precursor protein-mediated neurodegeneration. Since this neuroprotective effect is replicated by genetic knockdown and knockout of vem-1, the ortholog of progesterone receptor membrane component-1 (PGRMC1), it indicates that Sig2R ligands modulate a PGRMC1-related pathway. Last, we demonstrate that SAS-0132 improves cognitive performance both in the Thy-1 hAPP(L)(ond/Swe+) transgenic mouse model of AD and in healthy wild-type mice. These results demonstrate that Sig2R is a promising therapeutic target for neurocognitive disorders including AD. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/jnc.13917

    View details for PubMedID 27926996

  • Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist. Neuropharmacology Ardestani, P. M., Evans, A. K., Yi, B., Nguyen, T., Coutellier, L., Shamloo, M. 2017; 116: 371-386

    Abstract

    Degeneration of noradrenergic neurons occurs at an early stage of Alzheimer's Disease (AD). The noradrenergic system regulates arousal and learning and memory, and has been implicated in regulating neuroinflammation. Loss of noradrenergic tone may underlie AD progression at many levels. We have previously shown that acute administration of a partial agonist of the beta-1 adrenergic receptor (ADRB1), xamoterol, restores behavioral deficits in a mouse model of AD. The current studies examined the effects of chronic low dose xamoterol on neuroinflammation, pathology, and behavior in the pathologically aggressive 5XFAD transgenic mouse model of AD. In vitro experiments in cells expressing human beta adrenergic receptors demonstrate that xamoterol is highly selective for ADRB1 and functionally biased for the cAMP over the β-arrestin pathway. Data demonstrate ADRB1-mediated attenuation of TNF-α production with xamoterol in primary rat microglia culture following LPS challenge. Finally, two independent cohorts of 5XFAD and control mice were administered xamoterol from approximately 4.0-6.5 or 7.0-9.5 months, were tested in an array of behavioral tasks, and brains were examined for evidence of neuroinflammation, and amyloid beta and tau pathology. Xamoterol reduced mRNA expression of neuroinflammatory markers (Iba1, CD74, CD14 and TGFβ) and immunohistochemical evidence for microgliosis and astrogliosis. Xamoterol reduced amyloid beta and tau pathology as measured by regional immunohistochemistry. Behavioral deficits were not observed for 5XFAD mice. In conclusion, chronic administration of a selective, functionally biased, partial agonist of ADRB1 is effective in reducing neuroinflammation and amyloid beta and tau pathology in the 5XFAD model of AD.

    View details for DOI 10.1016/j.neuropharm.2017.01.010

    View details for PubMedID 28089846

    View details for PubMedCentralID PMC5385159

  • Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders. PloS one Yi, B. n., Jahangir, A. n., Evans, A. K., Briggs, D. n., Ravina, K. n., Ernest, J. n., Farimani, A. B., Sun, W. n., Rajadas, J. n., Green, M. n., Feinberg, E. N., Pande, V. S., Shamloo, M. n. 2017; 12 (7): e0180319

    Abstract

    The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.

    View details for PubMedID 28746336

  • A novel pharmacological tool blocks physiological mitochondrial fission through specifically inhibiting the Mff-Drp1 protein-protein interaction. Kornfeld, O. S., Qvit, N., Monbureau, M., Halpain, M., Shamloo, M., Mochly-Rosen, D. AMER SOC CELL BIOLOGY. 2017
  • The Golgi Outpost Protein TPPP Mediates Uniform Microtubule Polarity and Branching in Oligodendrocytes. Fu, M., Oses-Prieto, J. A., Lee, C., Saw, N. L., Shi, R., Nori, M., Shamloo, M., Burlingame, A., Barres, B. A. AMER SOC CELL BIOLOGY. 2017
  • A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice. Human molecular genetics Simmons, D. A., Belichenko, N. P., Ford, E. C., Semaan, S., Monbureau, M., Aiyaswamy, S., Holman, C. M., Condon, C., Shamloo, M., Massa, S. M., Longo, F. M. 2016; 25 (22): 4920-4938

    View details for DOI 10.1093/hmg/ddw316

    View details for PubMedID 28171570

    View details for PubMedCentralID PMC5418739

  • Potential biomarkers to follow the progression and treatment response of Huntington's disease. journal of experimental medicine Disatnik, M., Joshi, A. U., Saw, N. L., Shamloo, M., Leavitt, B. R., Qi, X., Mochly-Rosen, D. 2016

    Abstract

    Huntington's disease (HD) is a rare genetic disease caused by expanded polyglutamine repeats in the huntingtin protein resulting in selective neuronal loss. Although genetic testing readily identifies those who will be affected, current pharmacological treatments do not prevent or slow down disease progression. A major challenge is the slow clinical progression and the inability to biopsy the affected tissue, the brain, making it difficult to design short and effective proof of concept clinical trials to assess treatment benefit. In this study, we focus on identifying peripheral biomarkers that correlate with the progression of the disease and treatment benefit. We recently developed an inhibitor of pathological mitochondrial fragmentation, P110, to inhibit neurotoxicity in HD. Changes in levels of mitochondrial DNA (mtDNA) and inflammation markers in plasma, a product of DNA oxidation in urine, mutant huntingtin aggregates, and 4-hydroxynonenal adducts in muscle and skin tissues were all noted in HD R6/2 mice relative to wild-type mice. Importantly, P110 treatment effectively reduced the levels of these biomarkers. Finally, abnormal levels of mtDNA were also found in plasma of HD patients relative to control subjects. Therefore, we identified several potential peripheral biomarkers as candidates to assess HD progression and the benefit of intervention for future clinical trials.

    View details for PubMedID 27821553

  • Novel, selective EPO receptor ligands lacking erythropoietic activity reduce infarct size in acute myocardial infarction in rats PHARMACOLOGICAL RESEARCH Kiss, K., Csonka, C., Paloczi, J., Pipis, J., Goerbe, A., Kocsis, G. F., Murlasits, Z., Sarkoezy, M., Szucs, G., Holmes, C. P., Pan, Y., Bhandari, A., Csont, T., Shamloo, M., Woodburn, K. W., Ferdinandy, P., Bencsik, P. 2016; 113: 62-70

    Abstract

    Erythropoietin (EPO) has been shown to protect the heart against acute myocardial infarction in pre-clinical studies, however, EPO failed to reduce infarct size in clinical trials and showed significant safety problems. Here, we investigated cardioprotective effects of two selective non-erythropoietic EPO receptor ligand dimeric peptides (AF41676 and AF43136) lacking erythropoietic activity, EPO, and the prolonged half-life EPO analogue, darbepoetin in acute myocardial infarction (AMI) in rats. In a pilot study, EPO at 100U/mL significantly decreased cell death compared to vehicle (33.8±2.3% vs. 40.3±1.5%, p<0.05) in rat neonatal cardiomyocytes subjected to simulated ischemia/reperfusion. In further studies (studies 1-4), in vivo AMI was induced by 30min coronary occlusion and 120min reperfusion in male Wistar rats. Test compounds and positive controls for model validation (B-type natriuretic peptide, BNP or cyclosporine A, CsA) were administered iv. before the onset of reperfusion. Infarct size (IS) was measured by standard TTC staining. In study 1, 5000U/kg EPO reduced infarct size significantly compared to vehicle (45.3±4.8% vs. 59.8±4.5%, p<0.05). In study 2, darbepoetin showed a U-shaped dose-response curve with maximal infarct size-reducing effect at 5μg/kg compared to the vehicle (44.4±5.7% vs. 65.9±2.7%, p<0.01). In study 3, AF41676 showed a U-shaped dose-response curve, where 3mg/kg was the most effective dose compared to the vehicle (24.1±3.9% vs. 44.3±2.5%, p<0.001). The positive control BNP significantly decreased infarct size in studies 1-3 by approximately 35%. In study 4, AF43136 at 10mg/kg decreased infarct size, similarly to the positive control CsA compared to the appropriate vehicle (39.4±5.9% vs. 58.1±5.4% and 45.9±2.4% vs. 63.8±4.1%, p<0.05, respectively). This is the first demonstration that selective, non-erythropoietic EPO receptor ligand dimeric peptides AF41676 and AF43136 administered before reperfusion are able to reduce infarct size in a rat model of AMI. Therefore, non-erythropoietic EPO receptor peptide ligands may be promising cardioprotective agents.

    View details for DOI 10.1016/j.phrs.2016.08.013

    View details for Web of Science ID 000389086800006

  • Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome. Neuron Huang, W., Guenthner, C. J., Xu, J., Nguyen, T., Schwarz, L. A., Wilkinson, A. W., Gozani, O., Chang, H. Y., Shamloo, M., Luo, L. 2016; 92 (2): 392-406

    Abstract

    Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), which is associated with diverse neurodevelopmental and behavioral symptoms as well as obesity. RAI1 encodes a nuclear protein but little is known about its molecular function or the cell types responsible for SMS symptoms. Using genetically engineered mice, we found that Rai1 preferentially occupies DNA regions near active promoters and promotes the expression of a group of genes involved in circuit assembly and neuronal communication. Behavioral analyses demonstrated that pan-neural loss of Rai1 causes deficits in motor function, learning, and food intake. These SMS-like phenotypes are produced by loss of Rai1 function in distinct neuronal types: Rai1 loss in inhibitory neurons or subcortical glutamatergic neurons causes learning deficits, while Rai1 loss in Sim1(+) or SF1(+) cells causes obesity. By integrating molecular and organismal analyses, our study suggests potential therapeutic avenues for a complex neurodevelopmental disorder.

    View details for DOI 10.1016/j.neuron.2016.09.019

    View details for PubMedID 27693255

  • A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice. Human molecular genetics Simmons, D. A., Belichenko, N. P., Ford, E. C., Semaan, S., Monbureau, M., Aiyaswamy, S., Holman, C. M., Condon, C., Shamloo, M., Massa, S. M., Longo, F. M. 2016

    Abstract

    Decreases in the ratio of neurotrophic versus neurodegenerative signaling play a critical role in Huntington's disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75(NTR) signaling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75(NTR)-associated deleterious signaling and decreases survival signaling suggesting that p75(NTR) could be a valuable therapeutic target. This hypothesis was investigated by examining the effects of an orally bioavailable, small molecule p75(NTR) ligand, LM11A-31, on HD-related neuropathology in HD mouse models (R6/2, BACHD). LM11A-31 restored striatal AKT and other pro-survival signaling while inhibiting c-Jun kinase (JNK) and other degenerative signaling. Normalizing p75(NTR) signaling with LM11A-31 was accompanied by reduced Htt aggregates and striatal cholinergic interneuron degeneration as well as extended survival in R6/2 mice. The p75(NTR) ligand also decreased inflammation, increased striatal and hippocampal dendritic spine density, and improved motor performance and cognition in R6/2 and BACHD mice. These results support small molecule modulation of p75(NTR) as an effective HD therapeutic strategy. LM11A-31 has successfully completed Phase I safety and pharmacokinetic clinical trials and is therefore a viable candidate for clinical studies in HD.

    View details for PubMedID 27638888

  • An 8-week, open-label, dose-finding study of Nimodipine for the treatment of progranulin insufficiency from GRN gene mutations Sha, S., Miller, Z., Min, S., Zhou, Y., Mitic, L., Karydas, A., Koestler, M., Tsai, R., Corbetta-Rastelli, C., Lin, S., Hare, E., Brown, J., Fitch, R., Powers, R., Martens, L. H., Shamloo, M., Fagan, A., Farese, R., Seeley, W., Pearlman, R., Miller, B., Gan, L., Boxer, A. WILEY-BLACKWELL. 2016: 255–56
  • Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nature medicine Min, S., Chen, X., Tracy, T. E., Li, Y., Zhou, Y., Wang, C., Shirakawa, K., Minami, S. S., Defensor, E., Mok, S. A., Sohn, P. D., Schilling, B., Cong, X., Ellerby, L., Gibson, B. W., Johnson, J., Krogan, N., Shamloo, M., Gestwicki, J., Masliah, E., Verdin, E., Gan, L. 2015; 21 (10): 1154-1162

    Abstract

    Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early change in AD brains and a critical determinant in tau homeostasis and toxicity in mice. The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate were diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.

    View details for DOI 10.1038/nm.3951

    View details for PubMedID 26390242

  • Drug-controllable protein tags for the selective visualization or selective shutoff of newly synthesized proteins of interest in mammalian cells and in vivo Jacobs, C., Geng, Y., Badiee, R., Nguyen, T., Evans, A., Chung, H., Yang, Y., Shamloo, M., Tsien, R. Y., Lin, M. Z. WILEY-BLACKWELL. 2015: 230
  • Utilizing a novel peptide Inhibitor to modulate mitochondrial dynamics and investigate Drp1's physiological roles. Kornfeld, O. S., Qvit, N., Disatnik, M., Monbureau, M., Halpain, M., Evans, A., Shamloo, M., Rosen, D. AMER SOC CELL BIOLOGY. 2015
  • A death receptor 6-amyloid precursor protein pathway regulates synapse density in the mature CNS but does not contribute to Alzheimer's disease-related pathophysiology in murine models. journal of neuroscience Kallop, D. Y., Meilandt, W. J., Gogineni, A., Easley-Neal, C., Wu, T., Jubb, A. M., Yaylaoglu, M., Shamloo, M., Tessier-Lavigne, M., Scearce-Levie, K., Weimer, R. M. 2014; 34 (19): 6425-6437

    Abstract

    Recent studies implicate death receptor 6 (DR6) in an amyloid precursor protein (APP)-dependent pathway regulating developmental axon pruning, and in a pruning pathway operating during plastic rearrangements in adult brain. DR6 has also been suggested to mediate toxicity in vitro of Aβ peptides derived from APP. Given the link between APP, Aβ, and Alzheimer's disease (AD), these findings have raised the possibility that DR6 contributes to aspects of neurodegeneration in AD. To test this possibility, we have used mouse models to characterize potential function(s) of DR6 in the adult CNS and in AD-related pathophysiology. We show that DR6 is broadly expressed within the adult CNS and regulates the density of excitatory synaptic connections onto pyramidal neurons in a genetic pathway with APP. DR6 knock-out also gives rise to behavioral abnormalities, some of which are similar to those previously documented in APP knock-out animals. However, in two distinct APP transgenic models of AD, we did not observe any alteration in the formation of amyloid plaques, gliosis, synaptic loss, or cognitive behavioral deficits with genetic deletion of DR6, though we did observe a transient reduction in the degree of microglial activation in one model. Our results support the view that DR6 functions with APP to modulate synaptic density in the adult CNS, but do not provide evidence for a role of DR6 in the pathophysiology of AD.

    View details for DOI 10.1523/JNEUROSCI.4963-13.2014

    View details for PubMedID 24806669

  • ß1-adrenergic receptor activation enhances memory in Alzheimer's disease model. Annals of clinical and translational neurology Coutellier, L., Ardestani, P. M., Shamloo, M. 2014; 1 (5): 348-360

    Abstract

    Deficits in social recognition and learning of social cues are major symptoms of neurodegenerative disorders such as Alzheimer's disease (AD). Here we studied the role of β1-noradrenergic signaling in cognitive function to determine whether it could be used as a potential therapeutic target for AD.Using pharmacological, biochemical and behavioral tools, we assessed social recognition and the β1-adrenergic receptor (ADR) and its downstream PKA/phospho-CREB (pCREB) signaling cascade in the medial amygdala (MeA) in Thy1-hAPP(Lond/Swe+)(APP) mouse model of AD.Our results demonstrated that APP mice display a significant social recognition deficit which is dependent on the β1-adrenergic system. Moreover, betaxolol, a selective β1-ADR antagonist, impaired social but not object/odor learning in C57Bl/6 mice. Our results identifies activation of the PKA/pCREB downstream of β1-ADR in MeA as responsible signaling cascade for learning of social cues in MeA. Finally, we found that xamoterol, a selective β1-ADR partial agonist, rescued the social recognition deficit of APP mice by increasing nuclear pCREB.Our data indicate that activation of β1-ADR in MeA is essential for learning of social cues, and that an impairment of this cascade in AD may contribute to pathogenesis and cognitive deficits. Therefore, selective activation of β1-ADR may be used as a therapeutic approach to rescue memory deficits in AD. Further safety and translational studies will be needed to ensure the safety of this approach.

    View details for PubMedID 24883337

  • the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome CELL REPORTS Portmann, T., Yang, M., Mao, R., Panagiotakos, G., Ellegood, J., Dolen, G., Bader, P. L., Grueter, B. A., Goold, C., Fisher, E., Clifford, K., Rengarajan, P., Kalikhman, D., Loureiro, D., Saw, N. L., Zhou Zhengqui, Z. Q., Miller, M. A., Lerch, J. P., Henkelman, R. M., Shamloo, M., Malenka, R. C., Crawley, J. N., Dolmetsch, R. E. 2014; 7 (4): 1077-1092

    Abstract

    A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11(+/-)). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2(+)) and fewer dopamine-sensitive (Drd1(+)) neurons in deep layers of cortex. Electrophysiological recordings of Drd2(+) MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11(+/-) mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11(+/-) mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism.

    View details for DOI 10.1016/j.celrep.2014.03.036

    View details for Web of Science ID 000336495700018

  • 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

    Abstract

    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

  • Behavioral abnormalities and circuit defects in the Basal Ganglia of a mouse model of 16p11.2 deletion syndrome. Cell reports Portmann, T. n., Yang, M. n., Mao, R. n., Panagiotakos, G. n., Ellegood, J. n., Dolen, G. n., Bader, P. L., Grueter, B. A., Goold, C. n., Fisher, E. n., Clifford, K. n., Rengarajan, P. n., Kalikhman, D. n., Loureiro, D. n., Saw, N. L., Zhengqui, Z. n., Miller, M. A., Lerch, J. P., Henkelman, R. M., Shamloo, M. n., Malenka, R. C., Crawley, J. N., Dolmetsch, R. E. 2014; 7 (4): 1077–92

    Abstract

    A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11(+/-)). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2(+)) and fewer dopamine-sensitive (Drd1(+)) neurons in deep layers of cortex. Electrophysiological recordings of Drd2(+) MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11(+/-) mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11(+/-) mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism.

    View details for PubMedID 24794428

  • Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PloS one Izzo, N. J., Staniszewski, A., To, L., Fa, M., Teich, A. F., Saeed, F., Wostein, H., Walko, T., Vaswani, A., Wardius, M., Syed, Z., Ravenscroft, J., Mozzoni, K., Silky, C., Rehak, C., Yurko, R., Finn, P., Look, G., Rishton, G., Safferstein, H., Miller, M., Johanson, C., Stopa, E., Windisch, M., Hutter-Paier, B., Shamloo, M., Arancio, O., LeVine, H., Catalano, S. M. 2014; 9 (11)

    Abstract

    Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.

    View details for DOI 10.1371/journal.pone.0111898

    View details for PubMedID 25390368

    View details for PubMedCentralID PMC4229098

  • 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

    Abstract

    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

  • Inhibition of mitochondrial fragmentation diminishes Huntington's disease-associated neurodegeneration JOURNAL OF CLINICAL INVESTIGATION Guo, X., Disatnik, M., Monbureau, M., Shamloo, M., Mochly-Rosen, D., Qi, X. 2013; 123 (12): 5371-5388

    Abstract

    Huntington's disease (HD) is the result of expression of a mutated Huntingtin protein (mtHtt), and is associated with a variety of cellular dysfunctions including excessive mitochondrial fission. Here, we tested whether inhibition of excessive mitochondrial fission prevents mtHtt-induced pathology. We developed a selective inhibitor (P110-TAT) of the mitochondrial fission protein dynamin-related protein 1 (DRP1). We found that P110-TAT inhibited mtHtt-induced excessive mitochondrial fragmentation, improved mitochondrial function, and increased cell viability in HD cell culture models. P110-TAT treatment of fibroblasts from patients with HD and patients with HD with iPS cell-derived neurons reduced mitochondrial fragmentation and corrected mitochondrial dysfunction. P110-TAT treatment also reduced the extent of neurite shortening and cell death in iPS cell-derived neurons in patients with HD. Moreover, treatment of HD transgenic mice with P110-TAT reduced mitochondrial dysfunction, motor deficits, neuropathology, and mortality. We found that p53, a stress gene involved in HD pathogenesis, binds to DRP1 and mediates DRP1-induced mitochondrial and neuronal damage. Furthermore, P110-TAT treatment suppressed mtHtt-induced association of p53 with mitochondria in multiple HD models. These data indicate that inhibition of DRP1-dependent excessive mitochondrial fission with a P110-TAT-like inhibitor may prevent or slow the progression of HD.

    View details for DOI 10.1172/JCI70911

    View details for Web of Science ID 000327826100040

    View details for PubMedID 24231356

    View details for PubMedCentralID PMC3859413

  • A Small Molecule TrkB Ligand Reduces Motor Impairment and Neuropathology in R6/2 and BACHD Mouse Models of Huntington's Disease. journal of neuroscience Simmons, D. A., Belichenko, N. P., Yang, T., Condon, C., Monbureau, M., Shamloo, M., Jing, D., Massa, S. M., Longo, F. M. 2013; 33 (48): 18712-18727

    Abstract

    Loss of neurotrophic support in the striatum caused by reduced brain-derived neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease (HD) pathogenesis. BDNF acts via TrkB and p75 neurotrophin receptors (NTR), and restoring its signaling is a prime target for HD therapeutics. Here we sought to determine whether a small molecule ligand, LM22A-4, specific for TrkB and without effects on p75(NTR), could alleviate HD-related pathology in R6/2 and BACHD mouse models of HD. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to maximize brain levels. The ligand reached levels in the R6/2 forebrain greater than the maximal neuroprotective dose in vitro and corrected deficits in activation of striatal TrkB and its key signaling intermediates AKT, PLCγ, and CREB. Ligand-induced TrkB activation was associated with a reduction in HD pathologies in the striatum including decreased DARPP-32 levels, neurite degeneration of parvalbumin-containing interneurons, inflammation, and intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward climbing and grip strength compared with those given vehicle, though these groups had comparable rotarod performances and survival times. In BACHD mice, long-term LM22A-4 treatment (6 months) produced similar ameliorative effects. These results support the hypothesis that targeted activation of TrkB inhibits HD-related degenerative mechanisms, including spine loss, and may provide a disease mechanism-directed therapy for HD and other neurodegenerative conditions.

    View details for DOI 10.1523/JNEUROSCI.1310-13.2013

    View details for PubMedID 24285878

  • A Dramatic Increase of C1q Protein in the CNS during Normal Aging JOURNAL OF NEUROSCIENCE Stephan, A. H., Madison, D. V., Mateos, J. M., Fraser, D. A., Lovelett, E. A., Coutellier, L., Kim, L., Tsai, H., Huang, E. J., Rowitch, D. H., Berns, D. S., Tenner, A. J., Shamloo, M., Barres, B. A. 2013; 33 (33): 13460-13474

    Abstract

    The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.

    View details for DOI 10.1523/JNEUROSCI.1333-13.2013

    View details for Web of Science ID 000323155700021

    View details for PubMedCentralID PMC3742932

  • A dramatic increase of C1q protein in the CNS during normal aging. journal of neuroscience Stephan, A. H., Madison, D. V., Mateos, J. M., Fraser, D. A., Lovelett, E. A., Coutellier, L., Kim, L., Tsai, H., Huang, E. J., Rowitch, D. H., Berns, D. S., Tenner, A. J., Shamloo, M., Barres, B. A. 2013; 33 (33): 13460-13474

    Abstract

    The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.

    View details for DOI 10.1523/JNEUROSCI.1333-13.2013

    View details for PubMedID 23946404

  • GluN2B Antagonism Affects Interneurons and Leads to Immediate and Persistent Changes in Synaptic Plasticity, Oscillations, and Behavior. Neuropsychopharmacology Hanson, J. E., Weber, M., Meilandt, W. J., Wu, T., Luu, T., Deng, L., Shamloo, M., Sheng, M., Scearce-Levie, K., Zhou, Q. 2013; 38 (7): 1221-1233

    Abstract

    Although antagonists to GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) have been widely considered to be neuroprotective under certain pathological conditions, their immediate and lasting impacts on synaptic, circuit, and cognitive functions are poorly understood. In hippocampal slices, we found that the GluN2B-selective antagonist Ro25-6981 (Ro25) reduced synaptic NMDAR responses and consequently neuronal output in a subpopulation of GABAergic interneurons, but not pyramidal neurons. Consistent with these effects, Ro25 reduced GABAergic responses in pyramidal neurons and hence could affect circuit functions by altering the excitation/inhibition balance in the brain. In slices from Ts65Dn mice, a Down syndrome model with excess inhibition and cognitive impairment, acutely applied Ro25-rescued long-term potentiation (LTP) and gamma oscillation deficits, whereas prolonged dosing induced persistent rescue of LTP. In contrast, Ro25 did not impact LTP in wild-type (wt) mice but reduced gamma oscillations both acutely and following prolonged treatment. Although acute Ro25 treatment impaired memory performance in wt mice, memory deficits in Ts65Dn mice were unchanged. Thus, GluN2B-NMDARs contribute to the excitation/inhibition balance via impacts on interneurons, and blocking GluN2B-NMDARs can alter functions that depend on this balance, including synaptic plasticity, gamma oscillations, and memory. That prolonged GluN2B antagonism leads to persistent changes in synaptic and circuit functions, and that the influence of GluN2B antagonism differs between wt and disease model mice, provide critical insight into the therapeutic potential and possible liabilities of GluN2B antagonists.

    View details for DOI 10.1038/npp.2013.19

    View details for PubMedID 23340518

    View details for PubMedCentralID PMC3656364

  • A pharmacological screening approach for discovery of neuroprotective compounds in ischemic stroke. PloS one Beraki, S., Litrus, L., Soriano, L., Monbureau, M., To, L. K., Braithwaite, S. P., Nikolich, K., Urfer, R., Oksenberg, D., Shamloo, M. 2013; 8 (7)

    Abstract

    With the availability and ease of small molecule production and design continuing to improve, robust, high-throughput methods for screening are increasingly necessary to find pharmacologically relevant compounds amongst the masses of potential candidates. Here, we demonstrate that a primary oxygen glucose deprivation assay in primary cortical neurons followed by secondary assays (i.e. post-treatment protocol in organotypic hippocampal slice cultures and cortical neurons) can be used as a robust screen to identify neuroprotective compounds with potential therapeutic efficacy. In our screen about 50% of the compounds in a library of pharmacologically active compounds displayed some degree of neuroprotective activity if tested in a pre-treatment toxicity assay but just a few of these compounds, including Carbenoxolone, remained active when tested in a post-treatment protocol. When further examined, Carbenoxolone also led to a significant reduction in infarction size and neuronal damage in the ischemic penumbra when administered six hours post middle cerebral artery occlusion in rats. Pharmacological testing of Carbenoxolone-related compounds, acting by inhibition of 11-β-hydroxysteroid dehydrogenase-1 (11β-HSD1), gave rise to similarly potent in vivo neuroprotection. This indicates that the increase of intracellular glucocorticoid levels mediated by 11β-HSD1 may be involved in the mechanism that exacerbates ischemic neuronal cell death, and inhibiting this enzyme could have potential therapeutic value for neuroprotective therapies in ischemic stroke and other neurodegenerative disorders associated with neuronal injury.

    View details for DOI 10.1371/journal.pone.0069233

    View details for PubMedID 23874920

    View details for PubMedCentralID PMC3715457

  • FoxO6 regulates memory consolidation and synaptic function GENES & DEVELOPMENT Salih, D. A., Rashid, A. J., Colas, D., de la Torre-Ubieta, L., Zhu, R. P., Morgan, A. A., Santo, E. E., Ucar, D., Devarajan, K., Cole, C. J., Madison, D. V., Shamloo, M., Butte, A. J., Bonni, A., Josselyn, S. A., Brunet, A. 2012; 26 (24): 2780-2801

    Abstract

    The FoxO family of transcription factors is known to slow aging downstream from the insulin/IGF (insulin-like growth factor) signaling pathway. The most recently discovered FoxO isoform in mammals, FoxO6, is highly enriched in the adult hippocampus. However, the importance of FoxO factors in cognition is largely unknown. Here we generated mice lacking FoxO6 and found that these mice display normal learning but impaired memory consolidation in contextual fear conditioning and novel object recognition. Using stereotactic injection of viruses into the hippocampus of adult wild-type mice, we found that FoxO6 activity in the adult hippocampus is required for memory consolidation. Genome-wide approaches revealed that FoxO6 regulates a program of genes involved in synaptic function upon learning in the hippocampus. Consistently, FoxO6 deficiency results in decreased dendritic spine density in hippocampal neurons in vitro and in vivo. Thus, FoxO6 may promote memory consolidation by regulating a program coordinating neuronal connectivity in the hippocampus, which could have important implications for physiological and pathological age-dependent decline in memory.

    View details for DOI 10.1101/gad.208926.112

    View details for Web of Science ID 000312775700011

    View details for PubMedID 23222102

    View details for PubMedCentralID PMC3533081

  • A role for C1q in normal brain aging Stephan, A. H., Madison, D. V., Mateos, J., Fraser, D., Coutellier, L., Lovelett, E., Tsai, H., Huang, E., Rowitch, D., Kim, L., Tenner, A., Shamloo, M., Barres, B. A. ELSEVIER GMBH, URBAN & FISCHER VERLAG. 2012: 1133–33
  • Npas4: A Neuronal Transcription Factor with a Key Role in Social and Cognitive Functions Relevant to Developmental Disorders PLOS ONE Coutellier, L., Beraki, S., Ardestani, P. M., Saw, N. L., Shamloo, M. 2012; 7 (9)

    Abstract

    Npas4 is a transcription factor, which is highly expressed in the brain and regulates the formation and maintenance of inhibitory synapses in response to excitatory synaptic activity. A deregulation of the inhibitory-excitatory balance has been associated with a variety of human developmental disorders such as schizophrenia and autism. However, not much is known about the role played by inhibitory synapses and inhibitory pathways in the development of nervous system disorders. We hypothesized that alterations in the inhibitory pathways induced by the absence of Npas4 play a major role in the expression of the symptoms observed in psychiatric disorders. To test this hypothesis we tested mice lacking the transcription factor (Npas4 knock-out mice (Npas4-KO)) in a battery of behavioral assays focusing on general activity, social behaviors, and cognitive functions. Npas4-KO mice are hyperactive in a novel environment, spend less time exploring an unfamiliar ovariectomized female, spend more time avoiding an unfamiliar male during a first encounter, show higher social dominance than their WT littermates, and display pre-pulse inhibition, working memory, long-term memory, and cognitive flexibility deficits. These behavioral deficits may replicate schizophrenia-related symptomatology such as social anxiety, hyperactivity, and cognitive and sensorimotor gating deficits. Immunohistochemistry analyses revealed that Npas4 expression is induced in the hippocampus after a social encounter and that Npas4 regulates the expression of c-Fos in the CA1 and CA3 regions of the hippocampus after a cognitive task. Our results suggest that Npas4 may play a major role in the regulation of cognitive and social functions in the brain with possible implications for developmental disorders such as schizophrenia and autism.

    View details for DOI 10.1371/journal.pone.0046604

    View details for Web of Science ID 000309973900189

    View details for PubMedID 23029555

    View details for PubMedCentralID PMC3460929

  • Stratification substantially reduces behavioral variability in the hypoxic-ischemic stroke model. Brain and behavior Pollak, J., Doyle, K. P., Mamer, L., Shamloo, M., Buckwalter, M. S. 2012; 2 (5): 698-706

    Abstract

    Stroke is the most common cause of long-term disability, and there are no known drug therapies to improve recovery after stroke. To understand how successful recovery occurs, dissect candidate molecular pathways, and test new therapies, there is a need for multiple distinct mouse stroke models, in which the parameters of recovery after stroke are well defined. Hypoxic-ischemic stroke is a well-established stroke model, but behavioral recovery in this model is not well described. We therefore examined a panel of behavioral tests to see whether they could be used to quantify functional recovery after hypoxic-ischemic stroke. We found that in C57BL/6J mice this stroke model produces high mortality (approximately one-third) and variable stroke sizes, but is fast and easy to perform on a large number of mice. Horizontal ladder test performance on day 1 after stroke was highly and reproducibly correlated with stroke size (P < 0.0001, R(2) = 0.7652), and allowed for functional stratification of mice into a group with >18% foot faults and 2.1-fold larger strokes. This group exhibited significant functional deficits for as long as 3 weeks on the horizontal ladder test and through the last day of testing on automated gait analysis (33 days), rotarod (30 days), and elevated body swing test (EBST) (36 days). No deficits were observed in an automated activity chamber. We conclude that stratification by horizontal ladder test performance on day 1 identifies a subset of mice in which functional recovery from hypoxic-ischemic stroke can be studied.

    View details for DOI 10.1002/brb3.77

    View details for PubMedID 23139913

    View details for PubMedCentralID PMC3489820

  • Stratification substantially reduces behavioral variability in the hypoxic-ischemic stroke model BRAIN AND BEHAVIOR Pollak, J., Doyle, K. P., Mamer, L., Shamloo, M., Buckwalter, M. S. 2012; 2 (5): 698-706

    Abstract

    Stroke is the most common cause of long-term disability, and there are no known drug therapies to improve recovery after stroke. To understand how successful recovery occurs, dissect candidate molecular pathways, and test new therapies, there is a need for multiple distinct mouse stroke models, in which the parameters of recovery after stroke are well defined. Hypoxic-ischemic stroke is a well-established stroke model, but behavioral recovery in this model is not well described. We therefore examined a panel of behavioral tests to see whether they could be used to quantify functional recovery after hypoxic-ischemic stroke. We found that in C57BL/6J mice this stroke model produces high mortality (approximately one-third) and variable stroke sizes, but is fast and easy to perform on a large number of mice. Horizontal ladder test performance on day 1 after stroke was highly and reproducibly correlated with stroke size (P < 0.0001, R(2) = 0.7652), and allowed for functional stratification of mice into a group with >18% foot faults and 2.1-fold larger strokes. This group exhibited significant functional deficits for as long as 3 weeks on the horizontal ladder test and through the last day of testing on automated gait analysis (33 days), rotarod (30 days), and elevated body swing test (EBST) (36 days). No deficits were observed in an automated activity chamber. We conclude that stratification by horizontal ladder test performance on day 1 identifies a subset of mice in which functional recovery from hypoxic-ischemic stroke can be studied.

    View details for DOI 10.1002/brb3.77

    View details for Web of Science ID 000209174200016

    View details for PubMedCentralID PMC3489820

  • Deficits in Cognition and Synaptic Plasticity in a Mouse Model of Down Syndrome Ameliorated by GABA(B) Receptor Antagonists JOURNAL OF NEUROSCIENCE Kleschevnikov, A. M., Belichenko, P. V., Faizi, M., Jacobs, L. F., Htun, K., Shamloo, M., Mobley, W. C. 2012; 32 (27): 9217-9227

    Abstract

    Cognitive impairment in Down syndrome (DS) is characterized by deficient learning and memory. Mouse genetic models of DS exhibit impaired cognition in hippocampally mediated behavioral tasks and reduced synaptic plasticity of hippocampal pathways. Enhanced efficiency of GABAergic neurotransmission was implicated in those changes. We have recently shown that signaling through postsynaptic GABA(B) receptors is significantly increased in the dentate gyrus of Ts65Dn mice, a genetic model of DS. Here we examined a role for GABA(B) receptors in cognitive deficits in DS by defining the effect of selective GABA(B) receptor antagonists on behavior and synaptic plasticity of adult Ts65Dn mice. Treatment with the GABA(B) receptor antagonist CGP55845 restored memory of Ts65Dn mice in the novel place recognition, novel object recognition, and contextual fear conditioning tasks, but did not affect locomotion and performance in T-maze. The treatment increased hippocampal levels of brain-derived neurotrophic factor, equally in 2N and Ts65Dn mice. In hippocampal slices, treatment with the GABA(B) receptor antagonists CGP55845 or CGP52432 enhanced long-term potentiation (LTP) in the Ts65Dn DG. The enhancement of LTP was accompanied by an increase in the NMDA receptor-mediated component of the tetanus-evoked responses. These findings are evidence for a contribution of GABA(B) receptors to changes in hippocampal-based cognition in the Ts65Dn mouse. The ability to rescue cognitive performance through treatment with selective GABA(B) receptor antagonists motivates studies to further explore the therapeutic potential of these compounds in people with DS.

    View details for DOI 10.1523/JNEUROSCI.1673-12.2012

    View details for Web of Science ID 000306193900011

    View details for PubMedID 22764230

    View details for PubMedCentralID PMC3411326

  • 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

    Abstract

    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

    View details for PubMedCentralID PMC3345358

  • 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

    Abstract

    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