Blood-Borne Revitalization of the Aged Brain
2015; 72 (10): 1191-1194
CalFluors: A Universal Motif for Fluorogenic Azide Probes across the Visible Spectrum
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2015; 137 (22): 7145-7151
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
Aging-induced type I interferon response at the choroid plexus negatively affects brain function
2014; 346 (6205): 89-93
Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function
2014; 71 (10): 1228-1236
Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice
2014; 20 (6): 659-663
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
Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury.
Frontiers in neurology
2014; 5: 12-?
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 Web of Science ID 000337071000029
ApoE influences amyloid-ß (Aß) clearance despite minimal apoE/Aß association in physiological conditions.
Proceedings of the National Academy of Sciences of the United States of America
2013; 110 (19): E1807-16
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
In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis
Apolipoprotein E gene (APOE) alleles may shift the onset of Alzheimer's disease (AD) through apoE protein isoforms changing the probability of amyloid-? (A?) accumulation. It has been proposed that differential physical interactions of apoE isoforms with soluble A? (sA?) in brain fluids influence the metabolism of A?, providing a mechanism to account for how APOE influences AD risk. In contrast, we provide clear evidence that apoE and sA? interactions occur minimally in solution and in the cerebrospinal fluid of human subjects, producing apoE3 and apoE4 isoforms as assessed by multiple biochemical and analytical techniques. Despite minimal extracellular interactions with sA? in fluid, we find that apoE isoforms regulate the metabolism of sA? by astrocytes and in the interstitial fluid of mice that received apoE infusions during brain A? microdialysis. We find that a significant portion of apoE and sA? compete for the low-density lipoprotein receptor-related protein 1 (LRP1)-dependent cellular uptake pathway in astrocytes, providing a mechanism to account for apoE's regulation of sA? metabolism despite minimal evidence of direct interactions in extracellular fluids. We propose that apoE influences sA? metabolism not through direct binding to sA? in solution but through its actions with other interacting receptors/transporters and cell surfaces. These results provide an alternative frame work for the mechanistic explanations on how apoE isoforms influence the risk of AD pathogenesis.
View details for DOI 10.1073/pnas.1220484110
View details for PubMedID 23620513
Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood A beta clearance in a mouse model of beta-amyloidosis
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2012; 109 (38): 15502-15507
The APOE4 allele variant is the strongest known genetic risk factor for developing late-onset Alzheimer's disease. The link between apolipoprotein E (apoE) and Alzheimer's disease is likely due in large part to the impact of apoE on the metabolism of amyloid ? (A?) within the brain. Manipulation of apoE levels and lipidation within the brain has been proposed as a therapeutic target for the treatment of Alzheimer's disease. However, we know little about the dynamic regulation of apoE levels and lipidation within the central nervous system. We have developed an assay to measure apoE levels in the brain interstitial fluid of awake and freely moving mice using large molecular weight cut-off microdialysis probes.We were able to recover apoE using microdialysis from human cerebrospinal fluid (CSF) in vitro and mouse brain parenchyma in vivo. Microdialysis probes were inserted into the hippocampus of wild-type mice and interstitial fluid was collected for 36 hours. Levels of apoE within the microdialysis samples were determined by ELISA. The levels of apoE were found to be relatively stable over 36 hours. No apoE was detected in microdialysis samples from apoE KO mice. Administration of the RXR agonist bexarotene increased ISF apoE levels while ISF A? levels were decreased. Extrapolation to zero-flow analysis allowed us to determine the absolute recoverable concentration of apoE3 in the brain ISF of apoE3 KI mice. Furthermore, analysis of microdialysis samples by non-denaturing gel electrophoresis determined lipidated apoE particles in microdialysis samples were consistent in size with apoE particles from CSF. Finally, we found that the concentration of apoE in the brain ISF was dependent upon apoE isoform in human apoE KI mice, following the pattern apoE2>apoE3>apoE4.We are able to collect lipidated apoE from the brain of awake and freely moving mice and monitor apoE levels over the course of several hours from a single mouse. Our technique enables assessment of brain apoE dynamics under physiological and pathophysiological conditions and in response to therapeutic interventions designed to affect apoE levels and lipidation within the brain.
View details for DOI 10.1186/1750-1326-8-13
View details for Web of Science ID 000318657400001
View details for PubMedID 23601557
Human apoE Isoforms Differentially Regulate Brain Amyloid-beta Peptide Clearance
SCIENCE TRANSLATIONAL MEDICINE
2011; 3 (89)
The apolipoprotein E (APOE)-?4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-? (A?) accumulation. We recently demonstrated that the low-density lipoprotein receptor (LDLR) is a major apoE receptor in the brain that strongly regulates amyloid plaque deposition. In the current study, we sought to understand the mechanism by which LDLR regulates A? accumulation by altering A? clearance from brain interstitial fluid. We hypothesized that increasing LDLR levels enhances blood-brain barrier-mediated A? clearance, thus leading to reduced A? accumulation. Using the brain A? efflux index method, we found that blood-brain barrier-mediated clearance of exogenously administered A? is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous A? into the plasma of mice using an anti-A? antibody that prevents degradation of plasma A?, allowing its rate of appearance from the brain to be measured. Using this plasma A? accumulation technique, we found that LDLR overexpression enhances brain-to-blood A? transport. Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood A? clearance, which may serve as a useful therapeutic avenue in targeting A? clearance from the brain.
View details for DOI 10.1073/pnas.1206446109
View details for Web of Science ID 000309211000085
View details for PubMedID 22927427
Apolipoprotein E in Alzheimer's disease and other neurological disorders
2011; 10 (3): 241-252
The apolipoprotein E (APOE) ?4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ?4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-? (A?) peptide. In contrast, the APOE ?2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of A?(42) peptide. However, the mechanism by which APOE alleles differentially modulate A? accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral A? deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect A? clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of A? accumulation later in life. Performing in vivo microdialysis in a mouse model of A?-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble A? in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of A? deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble A? metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of A? deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and A? synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of A? from the brain, suggesting that A? clearance pathways may be useful therapeutic targets for AD prevention.
View details for DOI 10.1126/scitranslmed.3002156
View details for Web of Science ID 000292982100004
View details for PubMedID 21715678
Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular A beta Clearance
2009; 64 (5): 632-644
Apolipoprotein E (APOE) is a 299-aminoacid protein encoded by the APOE gene. Three common polymorphisms in the APOE gene, ?2, ?3, and ?4, result in a single aminoacid change in the APOE protein. APOE ?2, ?3, and ?4 alleles strongly alter, in a dose-dependent manner, the likelihood of developing Alzheimer's disease and cerebral amyloid angiopathy. In particular, APOE ?4 is associated with increased risk for Alzheimer's disease whereas APOE ?2 is associated with decreased risk. The effects of APOE genotype on risk of these diseases are likely to be mediated by differential effects of APOE on amyloid-? accumulation in the brain and its vasculature. Response to treatment for Alzheimer's disease might differ according to APOE genotype. Because convincing evidence ties the APOE genotype to risk of Alzheimer's disease and cerebral amyloid angiopathy, APOE has been studied in other neurological diseases. APOE ?4 is associated with poor outcome after traumatic brain injury and brain haemorrhage, although the mechanisms underlying these associations are unclear. The possibility that APOE has a role in these and other neurological diseases has been of great interest, but convincing associations have not yet emerged.
View details for Web of Science ID 000288482200012
View details for PubMedID 21349439
Apolipoprotein E (APOE) is the strongest genetic risk factor for Alzheimer's disease (AD). Previous studies suggest that the effect of apoE on amyloid-beta (A beta) accumulation plays a major role in AD pathogenesis. Therefore, understanding proteins that control apoE metabolism may provide new targets for regulating A beta levels. LDLR, a member of the LDL receptor family, binds to apoE, yet its potential role in AD pathogenesis remains unclear. We hypothesized that LDLR overexpression in the brain would decrease apoE levels, enhance A beta clearance, and decrease A beta deposition. To test our hypothesis, we created several transgenic mice that overexpress LDLR in the brain and found that apoE levels in these mice decreased by 50%-90%. Furthermore, LDLR overexpression dramatically reduced A beta aggregation and enhanced A beta clearance from the brain extracellular space. Plaque-associated neuroinflammatory responses were attenuated in LDLR transgenic mice. These findings suggest that increasing LDLR levels may represent a novel AD treatment strategy.
View details for DOI 10.1016/j.neuron.2009.11.013
View details for Web of Science ID 000273123700010
View details for PubMedID 20005821