A5006513220- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Parkinson's Disease Mechanisms and Treatments
- Extracellular vesicles in disease
- RNA Research and Splicing
- Neuroscience and Neuropharmacology Research
- MicroRNA in disease regulation
- Dementia and Cognitive Impairment Research
- Cellular transport and secretion
- Endoplasmic Reticulum Stress and Disease
- Cholinesterase and Neurodegenerative Diseases
- RNA regulation and disease
- Memory and Neural Mechanisms
- Neurological diseases and metabolism
- Autophagy in Disease and Therapy
- CRISPR and Genetic Engineering
- Genetics and Neurodevelopmental Disorders
- Mitochondrial Function and Pathology
- Neurogenetic and Muscular Disorders Research
- Advanced MRI Techniques and Applications
- Amyotrophic Lateral Sclerosis Research
- Genetic Neurodegenerative Diseases
- Advanced Neuroimaging Techniques and Applications
- Phosphodiesterase function and regulation
- Circular RNAs in diseases
Johns Hopkins Medicine
2020-2025
Johns Hopkins University
2019-2025
Brigham and Women's Hospital
2024
Hospital for Sick Children
2024
California University of Pennsylvania
2024
Rush University Medical Center
2024
Washington University in St. Louis
2024
Cleveland Clinic
2024
La Trobe University
2022
German Cancer Research Center
2022
Abstract Tau aggregation is a defining histopathological feature of Alzheimer’s disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this seed. We identified Bassoon (BSN), presynaptic scaffolding protein, as interactor seed isolated from mouse model tauopathy, progressive supranuclear palsy postmortem samples. show BSN...
Background: Clinical trials of anti-Aβ monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal (CSF) Aβ42/40.However, these measure deposits indirectly incompletely.In contrast, postmortem neuropathologic assessments allow direct investigation treatment effects on brain and many other pathologic features.Methods: From a clinical trial dominantly inherited AD, we measured...
Brain tissue-derived extracellular vesicles (bdEVs) play neurodegenerative and protective roles, including in Alzheimer's disease (AD). Extracellular (EVs) may also leave the brain to betray state of CNS periphery. Only a few studies have profiled proteome bdEVs source tissue. Additionally, focusing on bdEV cell type-specific surface markers are rare.We aimed reveal pathological mechanisms inside by profiling tissue proteomes AD patients. In addition, indicate targets for capturing molecular...
Extracellular vesicles (EVs) are released from different cell types in the central nervous system (CNS) and play roles regulating physiological pathological functions. Although brain-derived EVs (bdEVs) have been successfully collected brain tissue, there is not yet a "bdEV Atlas" of regions. To address this gap, we separated eight anatomical regions single individual subsequently characterized them by count, size, morphology, protein RNA content. The greatest particle yield was cerebellum,...
BackgroundPick's disease is a rare and predominantly sporadic form of frontotemporal dementia that classified as primary tauopathy. Pick's pathologically defined by the presence in frontal temporal lobes Pick bodies, composed hyperphosphorylated, three-repeat tau protein, encoded MAPT gene. has two distinct haplotypes, H1 H2; haplotype major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy corticobasal degeneration), H2 protective these disorders. The aim...
Abstract Reactive astrogliosis is a universal response of astrocytes to abnormal events and injuries. Studies have shown that proinflammatory microglia can polarize (designated A1 astrocytes) toward neurotoxic phenotype characterized by increased Complement Component 3 (C3) expression. It still unclear if inflammatory stimuli from other cell types may also be capable inducing subset C3 + astrocytes. Here, we show subtype induced activated endothelial cells distinct microglia. Furthermore,...
Pathologic α-synuclein plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson’s disease (PD). Disruption proteostasis is thought to be central pathologic toxicity; however, molecular mechanism this deregulation poorly understood. Complementary proteomic approaches cellular and animal models PD were used identify characterize interactome. We report that highest biological processes interacted with mice included RNA processing translation initiation. Regulation...
Abstract The spread of prion‐like protein aggregates is a common driver pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit clear progressive spreading pattern that correlates with severity. Clinical observation combined complementary experimental studies has shown preformed fibrils (PFF) are seeds propagate pathology by entering cells templating misfolding aggregation endogenous Tau. While several cell...
Alzheimer’s disease (AD) affects more than 10% of the population ≥65 y age, but underlying biological risks most AD cases are unclear. We show anti-poly-glycine-arginine (a-polyGR) positive aggregates frequently accumulate in sporadic autopsy brains (45/80 cases). hypothesize that these caused by one or polyGR-encoding repeat expansion mutations. developed a CRISPR/deactivated-Cas9 enrichment strategy to identify candidate GR-encoding mutations directly from genomic DNA isolated a-polyGR(+)...
Abstract This study presents a transcriptomic analysis of the cingulate cortex (CING) in Parkinson’s disease (PD) and dementia (PDD) using High-efficiency single-nucleus RNA sequencing (HiF-snRNA-seq) protocol optimized for post-mortem brain samples. quality prediction, poly-A tailing, dCas9-targeted depletion enabled 77 high-quality samples from 240 cases, yielding over 2 million nuclei classified into seven major cell types. Disease conditions revealed altered astrocyte microglia...
Mutations in PINK1 and parkin highlight the mitochondrial axis of Parkinson’s disease (PD) pathogenesis. PINK1/parkin regulation transcriptional repressor PARIS bears direct relevance to dopamine neuron survival through augmentation PGC-1α–dependent biogenesis. Notably, knockout attenuates dopaminergic neurodegeneration mouse models, indicating that interventions prevent accumulation could have therapeutic potential PD. To this end, we identified deubiquitinase cylindromatosis (CYLD) be a...
Abstract Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder clinically characterized by progressive postural instability, gaze palsy, parkinsonism, and cognitive decline caused degeneration in specific areas of the brain including globus pallidus (GP), substantia nigra, subthalamic nucleus. However, pathogenetic mechanism PSP remains unclear to date.Unbiased global proteome analysis patients' samples an important step toward understanding pathogenesis, as...
Abstract Asymptomatic Alzheimer’s disease (AsymAD) describes the status of individuals with preserved cognition but identifiable (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated postmortem brains a cohort AsymAD subjects to gain insight into mechanisms underlying resilience AD cognitive decline. Our results showed that cases exhibit enrichment in core decreased filamentous plaque accumulation,...
Variants of the apolipoprotein E (APOE) gene are greatest known risk factors for sporadic Alzheimer disease (AD). Three major APOE isoform alleles, ε2, ε3, and ε4, encode produce proteins that differ by only 1-2 amino acids but have different binding partner interactions. Whereas ε2 is protective against AD relative to ε4 associated with an increased development. However, role in regulation pathogenesis has remained largely undetermined. Extracellular vesicles (EVs) lipid bilayer-delimited...
Primary age-related tauopathy (PART) is characterized by aggregation of tau in the mesial temporal lobe older individuals. High pathologic stage (Braak stage) or a high burden hippocampal pathology has been associated with cognitive impairment PART. However, potential underlying mechanisms are not well understood. Cognitive many neurodegenerative diseases correlates synaptic loss, raising question whether loss also occurs To address this, we investigated changes Braak and PART using...
Abstract Fat embolism syndrome (FES) is a potentially life‐threatening condition that develops when fat leads to clinical symptoms and multisystem dysfunction. The classic triad of respiratory distress, neurologic symptoms, petechial rash are non‐specific, the lack specific laboratory tests makes diagnosis FES difficult. Although most common after long bone fractures, multiple conditions some which atraumatic have been associated with development FES. We report case occurred in setting...
Motivation: Important physical parameter, relaxometric constant$$$\;{D_r}$$$, linking magnetic susceptibility to induced transverse relaxation acceleration (i.e.,$$$\;{R2'}$$$) has not yet been fully understood in brain. Goal(s): To investigate underlying mechanisms affecting constant brain using temperature-dependent relaxometry and explore a better field-strength correction for ultra-high-field MRI. Approach: 3T 7T R2*/R2'/quantitative-susceptibility maps were acquired from post-mortem at...