A5074374069- Neuroinflammation and Neurodegeneration Mechanisms
- Alzheimer's disease research and treatments
- Neurological Disease Mechanisms and Treatments
- Single-cell and spatial transcriptomics
- Inflammation biomarkers and pathways
- Cholesterol and Lipid Metabolism
- interferon and immune responses
- Mitochondrial Function and Pathology
- Immune cells in cancer
- RNA Research and Splicing
- Computational Drug Discovery Methods
- Heat shock proteins research
- Neurogenesis and neuroplasticity mechanisms
- Cancer-related molecular mechanisms research
- Intracerebral and Subarachnoid Hemorrhage Research
- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
- Cholinesterase and Neurodegenerative Diseases
- Neuroscience and Neuropharmacology Research
- HIV/AIDS Research and Interventions
- Atherosclerosis and Cardiovascular Diseases
- Protein Structure and Dynamics
- HIV Research and Treatment
- Signaling Pathways in Disease
- RNA regulation and disease
Cornell University
2015-2024
Hangzhou Center for Disease Control and Prevention
2019-2024
Weill Cornell Medicine
2018-2024
MIND Research Institute
2015-2024
Rockefeller University
2002-2020
National Defense Medical Center
2020
Tri-Service General Hospital
2020
Wuhan Hankou Hospital
2014
Guangdong Provincial Hospital of Traditional Chinese Medicine
2014
Rockefeller Foundation
2010
Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize interactomes modified activity mutations that cause frontotemporal dementia (FTD) human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of...
Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB) signaling, by tau, drives microglial-mediated propagation and toxicity. Constitutive microglial NF-κB exacerbated, while inactivation diminished, seeding spreading young PS19 mice. Inhibition enhanced the retention reduced release...
Abstract Microglia have been shown to contribute the clearance of brain amyloid β peptides (Aβ), major component plaques, in Alzheimer’s disease (AD). However, it is not known whether microglia play a similar role tau, neurofibrillary tangles (NFTs). We now report that murine rapidly internalize and degrade hyperphosphorylated pathological tau isolated from AD tissue time-dependent manner vitro . further demonstrate readily human species released sections eliminate NFTs P301S tauopathy mice....
Abstract Splicing varies across brain regions, but the single-cell resolution of regional variation is unclear. We present a investigation differential isoform expression (DIE) between regions using long-read sequencing in mouse hippocampus and prefrontal cortex 45 cell types at postnatal day 7 ( www.isoformAtlas.com ). Isoform tests for DIE show better performance than exon tests. detect hundreds events traceable to types, often corresponding functionally distinct protein isoforms. Mostly,...
Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period cognitive resilience before the onset dementia. Here, we report that activation cyclic GMP-AMP synthase (cGAS) diminishes decreasing neuronal transcriptional network myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, part mediated cytosolic leakage mitochondrial DNA. Genetic ablation Cgas mice...
Abstract Single-nuclei RNA sequencing characterizes cell types at the gene level. However, compared to single-cell approaches, many single-nuclei cDNAs are purely intronic, lack barcodes and hinder study of isoforms. Here we present isoform (SnISOr-Seq). Using microfluidics, PCR-based artifact removal, target enrichment long-read sequencing, SnISOr-Seq increased barcoded, exon-spanning long reads 7.5-fold naive sequencing. We applied adult human frontal cortex found that exons associated...
Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered induced pluripotent stem cell (hiPSC)-derived neuronal lines express 4R Tau and carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive inclusions upon seeding with fibrils recapitulate features tauopathy phenotypes including shared transcriptomic signatures,...
Neurodegeneration, a result of multiple dysregulatory events, is lengthy multistep process manifested by accrual mutant variants and abnormal expression, posttranslational modification, processing certain proteins. Accumulation these dysregulated processes requires mechanism that maintains their functional stability allows the evolution neurodegenerative phenotype. In malignant cells, capacity to buffer transformation has been attributed heat-shock protein 90 (Hsp90). Although normal...
Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition to its well-characterized functions malignancy, recent evidence from several laboratories suggests role for maintaining the functional stability of neuronal proteins aberrant capacity, whether mutated or over-activated, allowing and sustaining accumulation toxic aggregates. addition, regulates activity transcription factor heat shock factor-1 (HSF-1), master regulator response, mechanism...
Hypertension (HTN) doubles the risk of Alzheimer’s disease (AD), but mechanisms remain unclear. Amyloid-β (Aβ), a key pathogenic factor in AD, induces cerebrovascular dysfunction. We hypothesized that HTN acts concert with Aβ to amplify its deleterious effects and increase production. Infusion angiotensin II (ANGII; intravenously) elevated blood pressure attenuated cerebral flow (CBF) response whisker stimulation or endothelium-dependent vasodilator acetylcholine (ACh) (P < 0.05)....
The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis single nuclei from brain tissues patients with AD carrying mutation or common (CV)–TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent previously identified disease-associated microglia (DAM) and hyperactivation AKT, one...
Genome-wide association studies of Alzheimer's disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular chemical mediators neuroinflammation remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling immunity. Cholesterol 25-hydroxylase (CH25H), enzyme responsible for 25-HC production, has...
Abstract Background Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer’s disease but also observed the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated CAA cellular source of reactive oxygen species (ROS) related signaling mechanisms remain unclear. We tested hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal leptomeningeal blood...
The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), R47H variant triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 TREM2
Optimal functioning of neuronal networks is critical to the complex cognitive processes memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular animal models as well human biospecimens show AD-related stressors mediate global disturbances dynamic intra- inter-neuronal through pathologic rewiring chaperome system into epichaperomes. These structures provide backbone upon which proteome-wide connectivity, turn, protein become disturbed ultimately...
The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with low tau pathology and slowdown of cognitive decline despite causal PSEN1 high levels amyloid beta in carrier1. However, molecular effects enabling E3S/S to confer protection remain unclear. Here, we replaced mouse Apoe wild-type human E3 or a tauopathy background. R136S markedly mitigated load protected against tau-induced synaptic loss, myelin spatial learning. Additionally, reduced microglial interferon response...
The apolipoprotein E4 (ApoE4) genotype combines with traumatic brain injury (TBI) to increase the risk of developing Alzheimer's Disease (AD). However, underlying mechanism(s) is not well-understood. We found that after exposure repetitive blast-induced TBI, phosphoinositol biphosphate (PIP2) levels in hippocampal regions young ApoE3 mice were elevated and associated reduction expression a PIP2 degrading enzyme, synaptojanin 1 (synj1). In contrast, ApoE4 did blast TBI. Following phospho-Tau...
Alzheimer’s disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. In this work, we used single-nuclei transcriptomics to dissect the contributions of chromosomes gonads in AD. a mouse model demyelination, identified roles modifying microglia oligodendrocyte responses before after myelin loss. an AD-related expressing APOE4, XY heightened interferon (IFN) response tau-induced demyelination. The X-linked gene, Toll-like receptor 7 ( Tlr7 ),...