A5089297674- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurological Disease Mechanisms and Treatments
- Dementia and Cognitive Impairment Research
- Historical Economic and Social Studies
- Neuroscience and Neuropharmacology Research
- Traumatic Brain Injury and Neurovascular Disturbances
- Traumatic Brain Injury Research
- Colonialism, slavery, and trade
- Advanced Neuroimaging Techniques and Applications
- S100 Proteins and Annexins
- Single-cell and spatial transcriptomics
- Cell Image Analysis Techniques
- Functional Brain Connectivity Studies
- Asian Studies and History
- Historical Studies on Reproduction, Gender, Health, and Societal Changes
- Posttraumatic Stress Disorder Research
- Prion Diseases and Protein Misfolding
- Monoclonal and Polyclonal Antibodies Research
- Virus-based gene therapy research
- Cholinesterase and Neurodegenerative Diseases
- Immune cells in cancer
- American Constitutional Law and Politics
- Historical Psychiatry and Medical Practices
- Intracerebral and Subarachnoid Hemorrhage Research
Harvard University
2017-2025
Massachusetts General Hospital
2017-2025
Film Independent
2024
University of Pennsylvania
2012-2024
MaineGeneral Medical Center
2017-2023
Alzheimer’s Disease Neuroimaging Initiative
2022-2023
Harvard NeuroDiscovery Center
2021
University of Warwick
2017
Canadian Armed Forces
2016
Washington University in St. Louis
2011-2015
The transition between soluble intrinsically disordered tau protein and aggregated in neurofibrillary tangles Alzheimer's disease is unknown. Here, we propose that species can undergo liquid-liquid phase separation (LLPS) under cellular conditions phase-separated droplets serve as an intermediate toward aggregate formation. We demonstrate phosphorylated or mutant aggregation prone recombinant undergoes LLPS, does high molecular weight phospho-tau isolated from human Alzheimer brain....
Repetitive mild or "concussive" traumatic brain injury (TBI) can cause substantial neurologic impairment, but the pathological features of this type are not fully understood. We report an experimental model TBI in which closed skulls anesthetized male C57BL/6J mice struck with electromagnetically controlled rubber impactor twice interval 24 hours between impacts. The had deficits Morris water maze performance first week after that only partially resolved 7 weeks later. By routine histology,...
Mixed pathology, with both Alzheimer's disease and vascular abnormalities, is the most common cause of clinical dementia in elderly. While usually thought to be concurrent diseases, fact that changes cerebral blood flow are a prominent early persistent alteration raises possibility alterations Alzheimer pathology more directly linked. Here, we report aged tau-overexpressing mice develop vessels including abnormal, spiraling morphologies; reduced vessel diameters; increased overall density...
Abstract Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, periphery largely liver. ApoE has been shown to impact integrity of blood–brain barrier, and, humans, APOE4 allele gene reported lead leaky barrier. We used specific knock-in mice expressing each common (human) alleles, longitudinal multiphoton intravital microscopy, directly monitor various isoforms on barrier integrity. found that humanized APOE4, but not APOE2 or APOE3,...
We observed enhanced tau spreading in the aging mouse brain and misfolding regions vulnerable Alzheimer’s disease.
Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide on the AAV9 with Cre cassette to enable sensitive detection of expression. After only two selection rounds delivered intravenously in transgenic mice carrying Cre-inducible fluorescent protein, we flow sorted cells from brain, and DNA sequencing revealed dominant capsids. One capsids, termed AAV-F, mediated expression...
Several studies have now supported the use of a tau lowering agent as possible therapy in treatment tauopathy disorders, including Alzheimer's disease. In human disease, however, concurrent amyloid-β deposition appears to synergize and accelerate pathological changes. Thus far, reduction strategies that been tested vivo examined setting pathology without confounding deposition. To determine whether reducing total expression transgenic model where there is plaque formation can still reduce...
Vascular endothelial cells play an important role in maintaining brain health, but their contribution to Alzheimer's disease (AD) is obscured by limited understanding of the cellular heterogeneity normal aged and disease. To address this, we performed single nucleus RNAseq on tissue from 32 human AD non-AD donors (19 female, 13 male) each with five cortical regions: entorhinal cortex, inferior temporal gyrus, prefrontal visual association primary cortex. Analysis 51,586 revealed unique gene...
Activation of inflammation pathways in the brain occurs Alzheimer's disease and may contribute to accumulation spread pathological proteins including tau. The goal this study was identify how changes microglia, a key inflammatory cell type, tau protein pathology-associated immune non-immune processes such as neuronal degeneration, astrocyte physiology, cytokine expression, blood vessel morphology. We used PLX3397 (290 mg/kg), colony-stimulating factor receptor 1 (CSF1R) inhibitor, reduce...
Alzheimer's Disease (AD) is associated with neuropathological changes, including aggregation of tau neurofibrillary tangles (NFTs) and amyloid-beta plaques. Mounting evidence indicates that vascular dysfunction also plays a key role in the pathogenesis progression AD, part through endothelial dysfunction. Based on findings animal models pathology induces abnormalities cellular senescence, we hypothesized human AD brain leads to senescence. To explore this hypothesis, isolated intact...
Neuronal tau reduction confers resilience against β-amyloid and tau-related neurotoxicity in vitro vivo. Here, we introduce a novel translational approach to lower expression of the gene MAPT at transcriptional level using gene-silencing zinc finger protein transcription factors (ZFP-TFs). Following single administration adeno-associated virus (AAV), either locally into hippocampus or intravenously enable whole-brain transduction, selectively reduced messenger RNA by 50 80% out 11 months,...
Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer's disease (AD) neuropathology remain unexplored. Here we performed single-nucleus RNA sequencing 628,943 astrocytes from five regions representing stereotypical AD pathology across 32 donors spanning entire normal aging severe continuum. We mapped out several unique astrocyte subclusters that exhibited varying responses AD-vulnerable neural network (spatial axis) or stage...
Abstract Human microglia are critically involved in Alzheimer’s disease (AD) progression, as shown by genetic and molecular studies. However, their role tau pathology progression human brain has not been well described. Here, we characterized 32 donors along of AD pathology, both time—from early to late pathology—and space—from entorhinal cortex (EC), inferior temporal gyrus (ITG), prefrontal (PFC) visual (V2 V1)—with biochemistry, immunohistochemistry, single nuclei-RNA-sequencing,...
Insoluble pathogenic proteins accumulate along blood vessels in conditions of cerebral amyloid angiopathy (CAA), exerting a toxic effect on vascular cells and impacting homeostasis. In this work, we provide new evidence from three-dimensional human brain histology that tau protein, the main component neurofibrillary tangles, can similarly segments. We quantitatively assessed n = 6 Alzheimer's disease (AD), normal aging control brains saw tau-positive vessel segments were present all AD...
Among other deficits, traumatic brain injury (TBI) causes impaired arousal and cognitive dysfunction. Hypothalamic orexin neuropeptides (also called hypocretins) regulate levels of arousal, cerebrospinal fluid are reportedly low in TBI patients. We hypothesized that acutely impairs the dynamics release into interstitial fluid, these extracellular correlate with wakefulness motor activity. To test this mice, we combined an electromagnetic controlled cortical impact (CCI) model experimental...
The pathological processes that lead to long-term consequences of multiple concussions are unclear. Primary mechanical damage axons during concussion is likely contribute dysfunction. Secondary has been hypothesized be induced or exacerbated by inflammation. main inflammatory cells in the brain microglia, a type macrophage. This research sought determine contribution microglia axon degeneration after repetitive closed-skull traumatic injury (rcTBI) using CD11b-TK (thymidine kinase) mice,...
Objective: More than 40,000 Canadian Armed Forces (CAF) personnel have deployed in support of the mission Afghanistan since 2002. Over same period, CAF strengthened its mental health system. This article explores effect these events on prevalence past-year disorders over period 2002-2013. Method: The data sources were 2 highly comparable population-based surveys Regular Force done 2002 and 2013 ( n = 5155 6996, respectively). Data collected via in-person interviews with Statistics Canada...
A prevailing hypothesis is that neurofibrillary tangles play a causal role in driving cognitive decline Alzheimer's disease (AD) because correlate anatomically with areas undergo neuronal loss. We used two-photon longitudinal imaging to directly test this and observed the fate of individual neurons two mouse models. At any time point, without died at >3 times rate as tangles. Additionally, prior dying, they became >20% more distant from neighboring across sessions. Similar microstructural...