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The impact of AD-associated genetic variants in 3D human mixed neural-glial models of AD

AD 相关遗传变异对 AD 3D 人类混合神经胶质模型的影响

基本信息

批准号：
10399510
负责人：
Doo Yeon Kim
金额：
$ 75.6万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2019-08-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10399510
关键词：
3-Dimensional Abeta clearance Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-42 Astrocytes Cell Death Cells Collection Coupled Data Data Set Etiology Family Gene Mutation Gene Proteins Genes Goals Human Human Genetics Immune Link Microfluidics Microglia Modeling Molecular Natural Immunity Nerve Degeneration Network-based Neurofibrillary Tangles Neurons Pathogenesis Pathogenicity Pathologic Pathway interactions Pharmaceutical Preparations Proteomics Role Small Interfering RNA Synapses System TREM2 gene Tauopathies Testing Tissues Variant astrogliosis case control chemokine cytokine cytotoxic epigenome exome sequencing functional genomics gene network genetic variant genome sequencing genome wide association study glial activation human stem cells innate immune pathways knock-down migration multiple omics neuroinflammation neuron loss neuropathology new therapeutic target novel recruit relating to nervous system risk variant transcriptome transcriptome sequencing whole genome

项目摘要

Title: The impact of AD-associated genetic variants in 3D human mixed neural-glial models of AD Project summary A growing number of Alzheimer’s disease (AD)-associated genes are associated with innate immunity and neuroinflammatory pathways. Network-based integrative analyses of AD-related genes have shown that microglial gene networks are strongly associated with AD neuropathology (1,5). We have shown that the protective AD-associated CD33 variant, rs3865444, leads to reduced CD33 expression and lower levels of Aβ42)(1). Conversely, microglial TREM2 variants, which increase AD risk, reduce microglial clearance of Ab. In addition to AD-linked functional variants in CD33 and TREM2, our AD whole genome sequencing (WGS) and whole exome sequencing (WES) datasets from AD families and case-controls, have revealed functional variants in AD-associated microglial genes linked to innate immunity and neuroinflammation, including CD33, TREM2, MS4A cluster, ABCA7, ABI3, PLGC2, CR1, and others. To test the impact of microglial genetic variants on AD pathogenesis on human genetic background, we developed a novel 3D human neuron- astrocyte-microglia tri-culture AD model using a unique 3D microfluidic system. We demonstrated that human microglial cells are recruited towards 3D AD (Ab-producing) neuron-astrocyte cultures via microglia-specific migration channels, in a chemokine-dependent manner, leading to neuroinflammation and neurodegeneration. Here, we propose to use our extensive collection of AD WGS and WES datasets, together with our 3D human tri-culture AD model, to evaluate the pathogenic effects of functional variants in AD-associated innate immune genes linked to neuroinflammation. In Aim 1, we will identify functional genomic variants and enriched gene networks that are linked to innate immunity and neuroinflammation. We will then examine the pathogenic roles of microglial AD risk or protective genes and their functional variants in 3D human mixed neural-astrocyte- microglial models of AD (Aim 2), explore AD pathogenic pathways that are linked to microglial AD risk genes and their functional variants using integrated multi-omics approaches, and validate selectively blocking these pathway (Aim 3). The overarching goals of this proposal are to comprehensively assess the pathogenic effects of functional variants in innate immune AD-risk genes on AD pathogenesis and explore underlying molecular networks, which will provide novel therapeutic targets for AD patients.

题目：AD相关基因变异在AD的3D人类混合神经胶质模型中的影响