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Neuronal Vulnerability to Lipid Droplets and Cholesterol in Alzheimer's Disease

阿尔茨海默病中神经元对脂滴和胆固醇的脆弱性

基本信息

批准号：
10644533
负责人：
Jubao Duan
金额：
$ 69.14万
依托单位：
NORTHSHORE UNIVERSITY HEALTHSYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644533
关键词：
ATAC-seq Affect Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker American Amyloid beta-Protein Astrocytes Biological Assay Biology Brain Diseases Cell Communication Cell Differentiation process Cell Line Cell Nucleus Cell Proliferation Cell Survival Cell model Cells Cellular Assay Cerebrum Cholesterol Cholesterol Esters Cholesterol Homeostasis Chromatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Data Dementia Demyelinations Disease Disease Progression Fatty Acids Genes Genetic Genetic Risk Genetic Transcription Goals Homeostasis Human Image Impairment Individual Induced pluripotent stem cell derived neurons Lesion Lipids Mediating Microglia Modeling Molecular Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nonesterified Fatty Acids Oligodendroglia Organoids Outcome Patients Phenotype Plasma Proteins RNA Research Role Small Nuclear RNA Stress Synapses Toxic effect Triglycerides aging brain aging population apolipoprotein E-4 brain health cell type clinical phenotype clinically relevant cohort dementia risk effective therapy epigenomics excitatory neuron genome wide association study genome-wide analysis induced pluripotent stem cell lipid metabolism multiple omics myelination nerve stem cell neural neuroprotection neuropsychiatry normal aging oligodendrocyte precursor polygenic risk score receptor remyelination repaired risk variant tau Proteins transcriptomics triacsin C

项目摘要

ABSTRACT Alzheimer's disease (AD) is a devastating neurodegenerative disorder that afflicts over 6.5 million Americans. Despite decades of research on amyloid-β (Aβ) and Tau lesions, effective treatment remains out of reach. Mounting AD genome-wide association studies (GWAS) risk loci provide opportunities for understanding disease biology and developing effective treatment. Multiple AD GWAS risk genes, such as APOE, are pivotal for lipid metabolism that is essential to brain health and disease. Under stress or in the aging brain, both astrocytes and microglia show abnormal lipid metabolism and accumulation of lipid droplets (LD). Although glial LD are known to be largely neuroprotective, LD formation in human neurons and its cellular and molecular ramifications are less clear. With excitatory neurons (Ex) derived from human induced pluripotent stem cells (iPSC), we have shown that APOE4 Ex neurons co-cultured with astrocytes accumulated more LD than APOE2/3 neurons. Our single-cell transcriptomic analysis of AD brain also identified an impaired neuron- oligodendrocyte precursor cell (OPC) communication mediated by APOE and its receptor LDLR. Interestingly, neural cholesterol was recently found to be essential to OPC proliferation and remyelination. We thus hypothesize that abnormal neuronal LD and cholesterol in AD contribute to neuronal damage and impaired neuron remyelination. Leveraging our expertise on using iPSC-derived neurons and cortical organoids as cellular models for brain disorders, we will characterize the cell type vulnerability to LD/cholesterol and the corresponding epigenomic/transcriptomic changes in the context of AD risk alleles. In Aim 1, to determine the neural vulnerability to LD and its clinical relevance in AD, we will co-culture Ex and Inhibitory (Inh) neurons of a cohort of 60 patient-specific iPSC lines, and assay neural LD, free fatty acids, cholesterol, and neural morphometrics, which will then be associated with APOE alleles and non-APOE AD polygenic risk scores. These cellular phenotypes will also be correlated with patients’ longitudinal plasma lipid levels and other clinical outcomes. In Aim 2, to understand molecular mechanisms underlying neural vulnerability to LD, we will perform single-cell RNA/ATAC-sequencing on the same neural co-cultures used in Aim 1 to identify genes with chromatin accessibility and transcription correlated with cellular LD in each cell type. In Aim 3, to examine the effect of AD risk alleles on cholesterol-mediated neuron-OPC communication and myelination, we will first use CRISPR editing to generate isogenic iPSC lines carrying AD risk alleles and then differentiate them into myelinating cerebral organoids. We will examine the effects of AD risk alleles on neuronal cholesterol levels as well as the OPC proliferation and neuron myelination. This study will significantly advance our understanding of the cellular and molecular mechanisms of neuronal vulnerability to abnormal LD and cholesterol in AD.

摘要