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：
10088365
负责人：
GUOJUN BU
金额：
$ 74.21万
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/10088365
关键词：
3-Dimensional Abeta clearance Address Affect 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 human old age (65+)in vivo in vivo Model induced pluripotent stem cell innovation loss of function middle age 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.

项目概要该提案的主要目标是解决 TREM2 介导的小胶质细胞功能在 TREM2 与大脑衰老和阿尔茨海默病 (AD) 病理发展的不同阶段有关。尽管取得了一些进展，但该基因及其一些与 AD 风险相关的罕见变异。 TREM2 特别是 TREM2-R47H 风险变异的分子病理学研究仍不清楚。在小鼠模型中检查 TREM2 功能丧失的影响支持不一致的结论； TREM2 缺陷会减少或增强淀粉样蛋白或 tau 蛋白病理学以及相关毒性，具体取决于病理发展阶段或特定小鼠模型，TREM2 介导的小胶质细胞。根据病理阶段，功能可能对淀粉样蛋白和 tau 蛋白病理产生动态影响在整个 AD 进展过程中，研究 TREM2-R47H 变异的影响的挑战进一步复杂化，最近的一项研究表明，将 R47H 突变引入小鼠 Trem2 基因位点会导致异常为了填补这些知识空白和缺乏适当的模型系统，我们已经生成了表达人 TREM2 或 TREM2- 的新型细胞类型特异性和可诱导小鼠模型小胶质细胞中的 R47H 为了解决人类相关性和分子机制，我们还生成了人类。因此，这是该研究的主要目标。该提案的目的是检查人类 TREM2 和 TREM2-R47H 对小胶质细胞和神经元的动态影响在衰老和 AD 中发挥作用；同时通过靶向和确定潜在的分子途径；我们认为 TREM2 介导的小胶质细胞功能具有保护作用。 AD 病理的发展，但当此类病理与突触相关时可能是不利的我们还认为 TREM2-R47H 特别代表功能丧失。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 TREM2 或 TREM2-R47H 对损伤范式和衰老过程的影响在目标 2 中，我们将检查 TREM2 或 TREM2-R47H 对 AD 病理的影响。在目标 3 中，我们研究了 Aβ 和 tau 在病理发展不同阶段的代谢、沉积和毒性。计划使用 iPSC 识别和验证与 TREM2 和 TREM2-R47H 相关的分子途径这项创新提案将采用衍生的小胶质细胞样细胞，无论其是否整合到大脑类器官中。我们现有的条件小鼠模型和 iPSC 衍生的细胞模型与状态相结合的优势最先进的技术，包括体内微透析、双光子显微镜和单光子分析细胞 RNA 测序。这些努力共同有助于理解 TREM2 如何调节小胶质细胞动态在衰老和 AD 发病机制中的作用以及我们如何针对这些途径来治疗 AD。