Demystifying Microglia in Aging and Alzheimer's Disease

揭秘小胶质细胞在衰老和阿尔茨海默病中的作用

基本信息

批准号：
9197047
负责人：
PHILIP L DE JAGER
金额：
$ 402.84万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197047
关键词：
Address Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid beta-Protein Animals Anti-Inflammatory Agents Anti-inflammatory Autopsy Behavior Behavioral Biological Assay Bone Marrow Brain CD14 gene Cell Lineage Cell Separation Cells ChIP-seq Classification Cognitive Complex Coupled Data Diabetes Mellitus Down-Regulation Employee Strikes Enhancers Etiology Gene Deletion Gene Expression Genes Genome Human Human Genome Immune Immune response Impaired cognition Individual Inflammation Inflammatory Learning Link Microglia Molecular Molecular Profiling Mus Myelogenous Myeloid Cells Nerve Degeneration Neurodegenerative Disorders Neurons Obesity Outcome Measure Pathologic Pathology Pathway interactions Patients Peptides Peripheral Phenotype Physiological Population Role Single Nucleotide Polymorphism Techniques Testing Training Untranslated RNA age related neurodegeneration aged aging brain brain cell cell type cognitive function epigenomics falls genetic variant genome wide association study healthy aging human data human disease human subject macrophage monocyte mouse model neurodegenerative phenotype neuroinflammation next generation novel programs relating to nervous system response risk variant therapeutic target tool transcriptome sequencing

项目摘要

Inflammation has become a well-recognized component of most neurodegenerative disorders, including Alzheimer's disease (AD). Until recently, we did not have the tools to reliably separate resident brain microglia from peripheral myeloid cells to delineate their functions in the brain. In this proposal, we will characterize different myeloid cell populations, such as resident brain microglia and peripheral monocytes, using elegant single-cell next-generation RNA sequencing (scRNA-Seq). We will determine the response of these neural immune components to physiological brain activity and neurodegeneration. Using novel models of mice with conditional targeting, we will manipulate AD risk genes specifically in brain microglia, and characterize the consequences, at both the single-cell and whole-animal level, in wildtype mice and mouse models of AD-like pathology. Importantly, we will compare these gene expression profiles to those obtained from over 500 well- studied healthy individuals and AD patients to assess the relevance of different monocyte phenotypes to the onset and progression of human AD.

炎症已成为大多数神经退行性疾病的公认组成部分，包括阿尔茨海默氏病（AD）。直到最近，我们还没有可靠地分开居民脑小胶质细胞的工具从周围髓样细胞描述它们在大脑中的功能。在此提案中，我们将描述使用优雅单细胞下一代RNA测序（SCRNA-SEQ）。我们将确定这些神经的反应生理大脑活性和神经变性的免疫成分。使用新颖的小鼠模型有条件的靶向，我们将在脑小胶质细胞中专门操纵AD风险基因，并表征在单细胞和全动物水平上，在野生型小鼠和AD样小鼠模型中的后果病理。重要的是，我们将将这些基因表达谱与从500多个井中获得的基因表达谱进行比较研究了健康的个体和AD患者，以评估不同的单核细胞表型与人类广告的发作和进展。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss.

携带 TREM2 R47H/ 突变的 iPSC 衍生的小胶质细胞具有促炎性并促进突触损失。

DOI：
10.1002/glia.24485
发表时间：
2024
期刊：
Glia
影响因子：
6.2
作者：
Penney,Jay;Ralvenius,WilliamT;Loon,Anjanet;Cerit,Oyku;Dileep,Vishnu;Milo,Blerta;Pao,Ping-Chieh;Woolf,Hannah;Tsai,Li-Huei
通讯作者：
Tsai,Li-Huei