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Deciphering isogenic APOE isoform dependent neurodegenerative response in human glia

破译人类神经胶质细胞中同基因 APOE 亚型依赖性神经退行性反应

基本信息

批准号：
9919510
负责人：
Julia TCW
金额：
$ 12.49万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919510
关键词：
AD transgenic mice Address Affect Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Apolipoprotein E Astrocytes Autophagocytosis Bioinformatics Biological Assay Brain Brain region CRISPR/Cas technology Cell Differentiation process Cell physiology Cells Clinical Clinical Trials Data Development Disease E protein Environment Exhibits Future Gene Expression Gene Expression Profiling Genetic Genetic Risk Genetic Transcription Genotype Goals Human In Vitro Infant Inflammation Inflammatory Response Inherited Knock-out Knowledge Late Onset Alzheimer Disease Lead Life Lipids Longitudinal Studies Membrane Lipids Metabolic Microglia Modality Modeling Molecular Myelin Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Organoids Pathogenesis Pathology Pathway Analysis Patients Phagocytes Phagocytosis Phenotype Population Production Protein Isoforms Regulation Research Research Project Grants Senile Plaques Series Signal Transduction Structure Symptoms System Systems Biology Testing Tissue-Specific Gene Expression Tissues Variant base brain cell cell injury cell type cytokine disorder risk embryo tissue genetic risk factor genetic signature genome editing gray matter human model imaging study induced pluripotent stem cell mouse model neuroimaging neuroinflammation novel therapeutics particle response risk variant single-cell RNA sequencing stem cell model tau Proteins tool transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY Apolipoprotein E (APOE) is the most significant risk gene for late-onset Alzheimer's disease (AD). APOE ɛ4/ɛ4 homozygosity increases AD risk by >14-fold. Although an association between the APOE ε4 allele and increased AD risk is well-established, the mechanisms underlying this genetic risk remain elusive. In brain, microglia and astrocytes induce inflammation and degrade (engulf, digest, store or recycle) lipid-rich cellular debris that accumulates during aging and neurodegeneration. We hypothesize that APOE ɛ4/ɛ4 genotype has cell autonomous effects on astrocytes and microglia which affects other cell types. Specifically, we hypothesize that APOE ε4/ε4 astrocytes and microglia exhibit altered response to lipid-rich debris (myelin fragments), detectable as changes in global transcription and cellular function. To test this hypothesis we have generated a unique series of isogenic iPSCs differing solely in APOE isoform using a CRISPR/Cas9 genome-editing tool. We have established a platform to recapitulate cellular systems of human brain in culture by differentiation of iPSC-derived astrocytes and microglia that express APOE. We seek to bring together this established patient- derived isogenic human iPSC model, powerful systems biology, bioinformatic approaches and in vitro metabolic assays including neuroinflammation, phagocytosis and autophagy to understand the mechanism underlying APOE risk for AD. This proposed research project sets out to unravel the APOE isoform-dependent effects in glia and their responses to lipid challenge. In aim 1, we will generate homogenous populations of astrocytes and microglia and mixed cultures of cortical neurons/glia from isogenic APOE isoforms and APOE knockout derived from patient iPSCs. We will perform differential gene expression analysis to determine the downstream effects of APOE genotype in each cell type. In aim 2, we will study APOE isoform-dependent glial responses to challenge with lipid-rich particles. Following an unbiased transcriptomic approach, we will analyze which of the disease associated microglia signatures or AD-associated networks are APOE isoform-dependent upon challenge. In aim 3, we will investigate APOE isoform-dependent effects on the inflammatory response and phagocytic/autolysosomal clearance of lipid particles. The goal of this project is to identify the transcriptomic networks and cellular functions governed by APOE genotype in the presence or absence of a disease relevant environment (myelin debris) to pinpoint the earliest and potentially most treatable mechanisms involved in AD pathogenesis.

项目总结