A5064624103- Neuroinflammation and Neurodegeneration Mechanisms
- Pluripotent Stem Cells Research
- Alzheimer's disease research and treatments
- Genetic Neurodegenerative Diseases
- Single-cell and spatial transcriptomics
- Tryptophan and brain disorders
- Mitochondrial Function and Pathology
- S100 Proteins and Annexins
- Immune Response and Inflammation
- Epigenetics and DNA Methylation
- Cholesterol and Lipid Metabolism
- CRISPR and Genetic Engineering
- Signaling Pathways in Disease
- Central Venous Catheters and Hemodialysis
- Autophagy in Disease and Therapy
- Atherosclerosis and Cardiovascular Diseases
- Anesthesia and Neurotoxicity Research
- NF-κB Signaling Pathways
- Nerve injury and regeneration
- Enzyme Structure and Function
- Shoulder Injury and Treatment
- Congenital heart defects research
- Muscle Physiology and Disorders
- Protein purification and stability
- Immune cells in cancer
Massachusetts Institute of Technology
2020-2024
Institute of Cognitive and Brain Sciences
2024
Washington University in St. Louis
2014-2020
Alzheimer's disease (AD) is the most common cause of dementia worldwide, but molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas aged human prefrontal cortex covering 2.3 million cells from postmortem brain samples 427 individuals with varying degrees AD pathology impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed...
Aging is a major risk factor in many forms of late-onset neurodegenerative disorders. The ability to recapitulate age-related characteristics human neurons culture will offer unprecedented opportunities study the biological processes underlying neuronal aging. Here, we show that using recently demonstrated microRNA-based cellular reprogramming approach, fibroblasts from postnatal near centenarian donors can be efficiently converted into maintain multiple age-associated signatures....
Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus transcriptomes epigenomes across 443 human subjects diverse Alzheimer's (AD) pathological phenotypes. We annotate 12 transcriptional states, including AD-dysregulated homeostatic, inflammatory, lipid-processing states. identify 1,542 AD-differentially-expressed genes, both microglia-state-specific disease-stage-specific alterations. By...
Abstract The glymphatic movement of fluid through the brain removes metabolic waste 1–4 . Noninvasive 40 Hz stimulation promotes neural activity in multiple regions and attenuates pathology mouse models Alzheimer’s disease 5–8 Here we show that multisensory gamma influx cerebrospinal efflux interstitial cortex 5XFAD model disease. Influx was associated with increased aquaporin-4 polarization along astrocytic endfeet dilated meningeal lymphatic vessels. Inhibiting clearance abolished removal...
Recent work has identified dozens of non-coding loci for Alzheimer's disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile epigenomic transcriptomic landscapes 850,000 nuclei from prefrontal cortexes 92 individuals with without to build a map the brain regulome, including profiles, regulators, co-accessibility modules, peak-to-gene links in cell-type-specific manner. We develop methods multimodal integration detecting...
DNA double-strand breaks (DSBs) are linked to neurodegeneration and senescence. However, it is not clear how DSB-bearing neurons influence neuroinflammation associated with neurodegeneration. Here, we characterize from the CK-p25 mouse model of using single-nucleus, bulk, spatial transcriptomic techniques. enter a late-stage damage response marked by nuclear factor κB (NFκB)-activated senescent antiviral immune pathways. In humans, Alzheimer's disease pathology closely activation in...
Approximately 40% of Alzheimers disease (AD) patients develop psychosis, yet the molecular and cellular processes that govern manifestation psychotic symptoms in dementia remain poorly understood. To define neurobiological correlates distinguish AD with psychosis (AD+P) from never exhibited (AD-P), we performed single-nucleus transcriptome epigenome profiling prefrontal cortex hippocampus 48 postmortem brains subjects segmented by psychiatric diagnosis. Our snRNA-seq uncovered differentially...
Abstract Motivation Reprogramming somatic cells into neurons holds great promise to model neuronal development and disease. The efficiency success rate of reprogramming, however, may vary between different conversion platforms cell types, thereby necessitating an unbiased, systematic approach estimate identity converted cells. Recent studies have demonstrated that long genes (>100 kb from transcription start end) are highly enriched in neurons, which provides opportunity identify...
Summary Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing late- onset Alzheimer’s disease and its expression in microglia associated with pro- inflammatory states. How interaction of APOE4 neurons differs from expressing disease-neutral allele APOE3 currently unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect impact neuron-microglia communication. Our results reveal that induces a distinct metabolic program marked by...
Breakdown of lipid homeostasis is thought to contribute pathological aging, the largest risk factor for neurodegenerative disorders such as Alzheimer's Disease (AD). Cognitive reserve theory posits a role compensatory mechanisms in aging brain preserving neuronal circuit functions, staving off cognitive decline, and mitigating AD. However, identities have remained elusive. A screen hippocampal dentate granule cell (DGC) synapse loss-induced factors identified secreted phospholipase
Abstract DNA double strand breaks (DSBs) are linked to aging, neurodegeneration, and senescence 1,2 . However, the role played by neurons burdened with DSBs in disease-associated neuroinflammation is not well understood. Here, we isolate harboring from CK-p25 mouse model of neurodegeneration through fluorescence-activated nuclei sorting (FANS), characterize their transcriptomes using single-nucleus, bulk, spatial sequencing techniques. We find that enter a late-stage damage response marked...