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A Human iPSC-Based Chimeric Mouse Model of Alzheimers Disease in Down Syndrome

基于人类 iPSC 的唐氏综合症阿尔茨海默病嵌合小鼠模型

基本信息

批准号：
10294441
负责人：
Peng Jiang
金额：
$ 200.84万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10294441
关键词：
Adult Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Animals Behavior Behavioral Brain Brain region CRISPR/Cas technology Candidate Disease Gene Cell Aging Chimera organism Chromosome 21 Data Development Disease Disease Progression Down Syndrome Electrophysiology (science)Excision Exhibits Exposure to Foundations Four-dimensional Functional disorder Gene Expression Gene Expression Profile General Population Genes Genetic Goals Hippocampal Formation Human Human Chromosomes IFNAR1 gene Imaging technology Impaired cognition Impairment Incentives Injections Interferons Knock-out Learning Life Link Mediating Memory Memory impairment Microglia Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Organoids Pathogenicity Pathologic Pathology Patients Performance Phenotype Plant Roots Population Presenile Alzheimer Dementia Reporting Research Risk Robotics Role Senile Plaques Signal Transduction Slice Synaptic plasticity Technology Testing Therapeutic Intervention Transgenic Mice Transplantation abeta accumulation aging brain base beta amyloid pathology brain tissue cytokine dosage genome editing genome wide association study human tissue hyperphosphorylated tau in vivo induced pluripotent stem cell insight macrophage microscopic imaging mouse model nerve stem cell neurotrophic factor new therapeutic target novel novel therapeutic intervention novel therapeutics prevent response risk variant robotic microscopy senescence single-cell RNA sequencing synaptic function synaptic pruning tau Proteins tau-1 tool transcriptome transcriptomics

项目摘要

Project Summary The goal of our study is to better understand the pathogenic role of human microglia in Alzheimer’s disease (AD) in Down syndrome (DS) and develop new therapeutic avenues for the treatment of AD in DS as well as AD in general population. Our studies are in line with the goals of RFA-OD-20-005 because we will focus on evaluating the genetic factors associated with trisomy 21 and their impacts on neurodegeneration using human tissue and a novel human-mouse chimeric brain model and we will also use gene editing to remove triplicated genes. The foundation of our studies is that recent genome-wide association studies have shown that many AD risk genes are highly and sometimes exclusively expressed by the brain-resident macrophage, microglia. Recent transcriptomic studies have also clearly demonstrated that human vs. mouse microglia exhibit distinct gene expression profiles, and more importantly, they age differently under both normal and diseased conditions. These findings argue for the utilization of species-specific research tools to investigate microglial functions in human brain aging and degeneration. We propose to use a novel human induced pluripotent stem cell (hiPSC)-based microglial chimeric mouse model that can recapitulate features of adult and aging human microglia to investigate the role of human microglia in AD in DS. While the aggregation of amyloid-beta (Ab) precedes that of tau, tau protein pathology commences in humans much sooner than was previously thought. Contrary to the marked microglial activation reported in amyloidogenic transgenic mouse models, in human brain tissue derived from AD and DS patients, brain regions particularly relevant in AD development, such as the hippocampal formation, exhibit low and late Ab pathology, whereas hyperphosphorylated tau (p-tau) accumulates starting in the early stages of the disease. The preferential accumulation of p-tau over Ab plaques could induce a totally different microglial response. Here we put forward a new tau/microglial senescence hypothesis that human microglial senescence and functional changes, induced by soluble p-tau, likely occur prior to neurodegeneration and is causatively linked to the AD progression and cognitive decline in DS. We have created control and DS microglial mouse chimeras by engrafting control and DS hiPSC-derived microglia into mouse brains. We will characterize the dynamic responses of DS and control hiPSC-derived microglia to pathological soluble p-tau in human microglial chimeric mouse brains, by using newly invented robotic four-dimensional long-term imaging technology. We will determine the changes in synaptic functions by electrophysiological recordings and behavioral performance of DS microglial chimeras after exposure to pathological soluble p-tau, as compared to control microglial chimeras. Moreover, single-cell RNA-sequencing analysis of chimeric mouse brains and CRISPR/Cas9-mediated removal of triplicated genes will be performed to determine the molecular mechanisms underlying the pathogenic role of microglia. By understanding the underpinning mechanisms, we can develop new therapeutic strategies to prevent human microglial senescence to slow the progression of AD in DS.

项目总结