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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.

项目概要我们研究的目的是更好地了解人类小胶质细胞在阿尔茨海默病 (AD) 中的致病作用唐氏综合症 (DS) 的研究，并开发治疗 DS 中的 AD 以及 AD 中的 AD 的新治疗途径一般人群。我们的研究符合 RFA-OD-20-005 的目标，因为我们将重点评估使用人体组织和与 21 三体相关的遗传因素及其对神经退行性变的影响一种新颖的人鼠嵌合大脑模型，我们还将使用基因编辑来删除三重基因。这我们研究的基础是，最近的全基因组关联研究表明，许多 AD 风险基因大脑驻留巨噬细胞小胶质细胞高度表达，有时仅表达。最近的转录组研究也清楚地表明，人类与小鼠小胶质细胞表现出不同的基因表达谱，更重要的是，它们在正常和患病条件下的衰老程度不同。这些研究结果支持利用物种特异性研究工具来研究人类小胶质细胞的功能大脑老化和退化。我们建议使用一种新型的基于人类诱导多能干细胞（hiPSC）的小胶质细胞嵌合小鼠模型可以概括成人和衰老人类小胶质细胞的特征以进行研究人类小胶质细胞在 AD 和 DS 中的作用。虽然 β 淀粉样蛋白 (Ab) 的聚集先于 tau 的聚集，但 tau 蛋白的聚集蛋白质病理学在人类中的出现比之前想象的要早得多。与标注相反在淀粉样蛋白转基因小鼠模型和来自以下来源的人脑组织中报道了小胶质细胞激活 AD 和 DS 患者，与 AD 发展特别相关的大脑区域，例如海马结构，表现出低和晚期 Ab 病理学，而过度磷酸化 tau (p-tau) 则在早期开始积累疾病的阶段。 p-tau 相对于 Ab 斑块的优先积累可能会导致完全不同的结果。小胶质细胞反应。在这里我们提出了一个新的tau/小胶质细胞衰老假说，即人类小胶质细胞由可溶性 p-tau 诱导的衰老和功能变化可能发生在神经变性之前，并且是与 AD 进展和 DS 认知能力下降有因果关系。我们已经创建了对照和 DS 小胶质细胞通过将对照和 DS hiPSC 衍生的小胶质细胞移植到小鼠大脑中来构建小鼠嵌合体。我们将表征 DS 和对照 hiPSC 衍生的小胶质细胞对人类病理性可溶性 p-tau 的动态反应小胶质细胞嵌合小鼠大脑，通过使用新发明的机器人四维长期成像技术。我们将通过电生理记录确定突触功能的变化 DS 小胶质细胞嵌合体暴露于病理性可溶性 p-tau 后的行为表现，与控制小胶质细胞嵌合体。此外，嵌合小鼠大脑的单细胞 RNA 测序分析和将进行 CRISPR/Cas9 介导的三重基因去除以确定分子机制小胶质细胞致病作用的基础。通过了解基础机制，我们可以开发预防人类小胶质细胞衰老以减缓 DS 中 AD 进展的新治疗策略。