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.

项目摘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氏病（AD）中的致病作用（AD）在唐氏综合症（DS）中，开发了新的治疗途径，用于DS和AD中的AD治疗一般人口。我们的研究符合RFA-OD-20-005的目标，因为我们将专注于评估与21三体术相关的遗传因素及其对使用人体组织和一种新型的人鼠嵌合脑模型，我们还将使用基因编辑来去除一致的基因。我们研究的基础是，最近全基因组关联研究表明许多AD风险基因高度，有时是由脑居民巨噬细胞小胶质细胞表达的。最近的转录组研究还清楚地表明，人与小鼠小胶质细胞暴露了不同的基因表达谱，更重要的是，它们在正常和患病状况下的年龄不同。这些调查结果主张利用规格特定的研究工具来研究人类的小胶质细胞功能大脑衰老和变性。我们建议使用新型人类诱导的多能干细胞（HIPSC）可以概括成人和衰老的人类小胶质细胞特征的小胶质嵌合小鼠模型人类小胶质细胞在DS中的作用。而淀粉样β（AB）的聚集在tau的前面蛋白质病理在人类中的开始比以前想象的要早得多。与标记的在淀粉样蛋白原转基因小鼠模型中报道的小胶质细胞激活，源自人脑组织 AD和DS患者，大脑区域在AD发育中特别相关，例如海马形成，表现出低和晚期的AB病理学，而热磷酸化的TAU（P-TAU）从早期开始积累疾病的阶段。 P-TAU比AB斑块的首选积累可能会引起完全不同的小胶质响应。在这里，我们提出了一个新的tau/小胶质敏感假设，即人类小胶质细胞固体p-tau诱导的感应和功能变化可能发生在神经变性之前，IS 与DS的AD进展和认知下降的因果关系。我们创建了控制和DS小胶质细胞小鼠嵌合体通过将控制和DS HIPSC衍生的小胶质细胞植入小鼠大脑中。我们将表征 DS和控制HIPSC衍生的小胶质细胞对人类病理固体P-TAU的动态反应小胶质嵌合小鼠大脑，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和暴露于病理固体p-tau后，DS小胶质细胞嵌合体的行为表现，与控制小胶质嵌合体。此外，嵌合小鼠大脑的单细胞RNA测序分析和将进行CRISPR/CAS9介导的三式三份基因的去除，以确定分子机制小胶质细胞的致病作用。通过了解基础机制，我们可以发展新的治疗策略，以防止人类小胶质细胞敏感，以减慢DS中AD的进展。