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TREM2-mediated microglial dynamic function in Alzheimer disease

TREM2 介导的阿尔茨海默病小胶质细胞动态功能

基本信息

批准号：
9914464
负责人：
GUOJUN BU
金额：
$ 75.62万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914464
关键词：
3-Dimensional Abeta clearance Address Affect Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Apolipoprotein E Behavior Biochemical Biological Models Brain CRISPR/Cas technology Cell Line Cell model Cells Cerebrum Cognitive Dementia Deposition Development Disease Disease Progression Electrophysiology (science)Etiology Future Gene Delivery Genes Goals Human Image Immune Immune response In Vitro Inflammatory Response Injury Knock-in Knock-out Knowledge Mediating Messenger RNA Metabolism Methods Microdialysis Microglia Modeling Molecular Molecular Profiling Molecular Target Morphology Mus Mutation Nerve Degeneration Neurons Organoids Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Phagocytosis Pharmacology Population Process RNA Splicing Role Senile Plaques Societies Synapses System TREM2 gene Tauopathies Techniques Technology Testing Toxic effect Validation Variant abeta deposition abeta toxicity aging brain amyloid formation amyloid pathology base cell type density genetic risk factor genomic locus human model in vivo in vivo Model induced pluripotent stem cell innovation loss of function mouse model novel rare variant risk variant single-cell RNA sequencing stem cell model tau Proteins transcriptome sequencing treatment strategy two photon microscopy two-photon

项目摘要

PROJECT SUMMARY The major goal of this proposal is to address the dynamic role of TREM2-mediated microglial function in brain aging and during different stages of the pathological development of Alzheimer’s disease (AD). TREM2 is a microglial specific gene with several of its rare variants associated with AD risk. Despite some progress, the molecular pathobiology of TREM2 in particular the TREM2-R47H risk variant is still not clear. Studies examining the effects of loss of TREM2 function in mouse models support inconsistent conclusions; with TREM2 deficiency either reduces or enhances amyloid or tau pathology and associated toxicity depending on the stage of the pathological development or the specific mouse models. As such, TREM2-mediated microglial function likely has dynamic effects on amyloid and tau pathologies depending on pathological stages throughout AD progression. Further complicating the challenge of studying the impact of TREM2-R47H variant, a recent study revealed that introducing the R47H mutation into the mouse Trem2 gene locus leads to aberrant splicing and instability of its mRNA. To fill these gaps in knowledge and the lack of appropriate model systems, we have generated novel cell type-specific and inducible mouse models expressing human TREM2 or TREM2- R47H in microglia. To address human relevance and molecular mechanisms, we have also generated human induced pluripotent stem cell (iPSC) lines carrying TREM2 or TREM2-R47H. Thus, the major goal of this proposal is to examine the dynamic effects of human TREM2 and TREM2-R47H on microglial and neuronal functions in aging and AD; while in the process defines the underlying molecular pathways by targeted and non-targeted approaches. We hypothesize that TREM2-mediated microglial function is protective against the development of AD pathologies but can be detrimental when such pathologies are associated with synaptic loss and neurodegeneration. We also hypothesize that TREM2-R47H represents a loss-of-function in particular in microglia-mediated protection against AD-related pathways. We will test our hypothesis through three aims. In Aim 1, we plan to analyze the effects of TREM2 or TREM2-R47H upon injury paradigms and during aging in the absence of AD pathology. In Aim 2, we will examine the effects of TREM2 or TREM2-R47H on the metabolism, deposition, and toxicity of Aβ and tau at different stages of pathological development. In Aim 3, we plan to identify and validate the molecular pathways associated with TREM2 and TREM2-R47H using iPSC- derived microglia-like cells with or without integration into cerebral organoids. This innovative proposal will take advantage of our existing conditional mouse models and iPSC-derived cellular models combined with state-of- the-art technologies including in vivo microdialysis, two-photon microscopy and molecular profiling by single cell RNA-Seq. These efforts should collectively help to understand how TREM2 modulates microglial dynamic roles in aging and AD pathogenesis and how we can target these pathways to treat AD.

项目摘要该提案的主要目标是解决TREM 2介导的小胶质细胞功能在神经系统疾病中的动态作用。脑老化和阿尔茨海默病（AD）病理发展的不同阶段。trem 2是一种小胶质细胞特异性基因，其几种罕见变异与AD风险相关。尽管取得了一些进展， TREM 2的分子病理学，特别是TREM 2-R47 H风险变体仍然不清楚。研究在小鼠模型中检查TREM 2功能丧失的影响支持不一致的结论; TREM 2缺乏减少或增强淀粉样蛋白或tau病理学和相关毒性，这取决于病理发展阶段或特定小鼠模型。因此，TREM 2介导的小胶质细胞功能可能对淀粉样蛋白和tau病理具有动态影响，这取决于病理阶段在AD的发展过程中。进一步使研究TREM 2-R47 H变体的影响的挑战复杂化，最近的一项研究表明，将R47 H突变引入小鼠Trem 2基因位点会导致异常的其mRNA的剪接和不稳定性。为了填补这些知识空白和缺乏适当的模型系统，我们已经产生了表达人TREM 2或TREM 2的新的细胞类型特异性和诱导型小鼠模型，小胶质细胞中的R47 H。为了解决人类相关性和分子机制，我们还产生了人类携带TREM 2或TREM 2-R47 H的诱导多能干细胞（iPSC）系。因此，本项目的主要目标一个提议是检查人TREM 2和TREM 2-R47 H对小胶质细胞和神经元细胞的动态作用。在衰老和AD中发挥作用;而在此过程中，通过靶向和非针对性的方法。我们假设TREM 2介导的小胶质细胞功能是保护性的， AD病理的发展，但当这种病理与突触相关时可能是有害的。丧失和神经退化。我们还假设TREM 2-R47 H特别代表功能丧失，小胶质细胞介导的对AD相关通路的保护作用。我们将通过三个目标来检验我们的假设。在目标1中，我们计划分析TREM 2或TREM 2-R47 H对损伤范例和在衰老过程中的作用，没有AD病理学。在目的2中，我们将检查TREM 2或TREM 2-R47 H对细胞增殖的影响。 Aβ和tau在不同病理发展阶段的代谢、沉积和毒性。在目标3中，我们计划使用iPSC鉴定和验证与TREM 2和TREM 2-R47 H相关的分子途径- 衍生的小胶质细胞样细胞，有或没有整合到大脑类器官中。这一创新举措将我们现有的条件性小鼠模型和iPSC衍生的细胞模型结合了现有技术包括体内微透析、双光子显微镜和通过单光子显微镜的分子谱分析，细胞RNA测序这些努力应该共同帮助理解TREM 2如何调节小胶质细胞动力学在衰老和AD发病机制中的作用，以及我们如何靶向这些途径来治疗AD。