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.

项目摘要该提案的主要目的是解决trem2介导的小胶质函数的动态作用脑老化以及阿尔茨海默氏病（AD）病理发展的不同阶段。 trem2是小胶质细胞基因，其几种与AD风险相关的稀有变体。尽管有一些进展， TREM2的分子病理生物学尤其是TREM2-R47H风险变体尚不清楚。研究检查小鼠模型中TREM2功能丧失的影响支持不一致的结论；和 TREM2缺乏可减少或增强淀粉样蛋白或TAU病理学，并根据病理发育或特定小鼠模型的阶段。因此，Trem2介导的小胶质细胞功能可能会对淀粉样蛋白和TAU病理具有动态影响，具体取决于病理阶段通过广告进展。进一步使研究trem2-r47h变体的影响的挑战更加复杂，最近的一项研究表明，将R47H突变引入小鼠TREM2基因座导致异常其mRNA的剪接和不稳定性。为了填补知识和缺乏适当模型系统的这些空白，我们已经产生了表达人trem2或trem2-的新型细胞类型特异性和诱导小鼠模型小胶质细胞中的R47H。为了解决人类的相关性和分子机制，我们还产生了人类携带TREM2或TREM2-R47H的诱导多能干细胞（IPSC）系。那是主要目标建议是检查人类Trem2和Trem2-R47H对小胶质细胞和神经元的动态影响衰老和广告的功能；在此过程中，通过靶向和非目标方法。我们假设Trem2介导的小胶质细胞功能受到保护 AD病理学的发展，但当这种病理与突触相关时可能有害损失和神经变性。我们还假设TREM2-R47H尤其代表了功能丧失在小胶质细胞介导的针对AD相关途径的保护中。我们将通过三个目标检验我们的假设。在AIM 1中，我们计划分析trem2或trem2-r47h对损伤范式的影响以及在衰老期间缺乏广告病理学。在AIM 2中，我们将检查TREM2或TREM2-R47H对在病理发育的不同阶段，Aβ和TAU的代谢，沉积和毒性。在AIM 3中，我们计划使用IPSC-识别和验证与Trem2和Trem2-R47H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器官中。这个创新的建议将采取我们现有的条件小鼠模型和IPSC衍生的细胞模型的优势与最新的细胞模型相结合艺术技术，包括体内微透析，两光子显微镜和单个分子分析细胞RNA-seq。这些努力应该共同帮助了解TREM2如何调节小胶质动态在衰老和AD发病机理中的作用，以及我们如何靶向这些治疗AD的途径。