Dissecting neuron-microglia-astrocyte interaction in AD pathogenesis

解析 AD 发病机制中神经元-小胶质细胞-星形胶质细胞的相互作用

• 批准号: 10744531
• 负责人: JUNMIN PENG
• 金额: $ 45.5万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10744531
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Arctic Regions; Astrocytes; Biological Markers; Blood Vessels; Brain; Cause of Death; Cell Communication; Cells; Dementia; Disease; Flow Cytometry; Goals; Grant; Knock-in Mouse; Label; Methods; Microglia; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neuronal Dysfunction; Neurons; Outcome; Pathogenesis; Pathology; Pathway interactions; Population; Proteome; Proteomics; Senile Plaques; Swedish mutation; Technology; Tissues; United States; brain tissue; cell type; effective therapy; mouse model; novel; novel therapeutic intervention; response

PROJECT SUMMARY/ABSTRACT The goal of this grant supplement is to investigate the dysfunction of neuron-microglia-astrocyte interaction contributing to pathogenesis of Alzheimer’s disease (AD), by performing cell-type specific proteomic profiling of a new animal model of Alzheimer’s disease. Recently, an App knock-in mouse model (APP-SAA KI) has been generated to express humanized APP with three familial mutations: KM670/671NL (Swedish), E693G (Arctic) and T714I (Austrian). The model displays critical AD-related pathologies, including amyloid plaques in brain and vascular tissues, astroglial and microglial responses, and CSF biomarkers of neurodegeneration, providing an opportunity of studying neuron-microglia-astrocyte interaction in response to AD-relevant pathology. We propose to deeply profile the proteomes of neurons, microglia, astrocytes, and the whole brain tissues in the AppSAA mice at different ages, utilizing our newly developed proximity labeling and the traditional flow cytometry method. Successful outcome of this project will identify novel, cell type specific molecular components and pathways regulating cell-cell interactions during AD pathogenesis, which may provide new therapeutic strategies for effective treatment of this devastating disorder.

项目总结/摘要 这项补助金补充的目标是调查神经元-小胶质细胞-星形胶质细胞相互作用的功能障碍 有助于阿尔茨海默病（AD）的发病机制，通过进行细胞类型特异性蛋白质组学分析， 一种新的阿尔茨海默病动物模型近日，一款App敲入小鼠模型（APP-SAA KI）在 产生以表达具有三个家族性突变的人源化APP：KM 670/671 NL（瑞典）、E693 G（北极） T714 I（奥地利）该模型显示了关键的AD相关病理，包括脑中的淀粉样蛋白斑块， 血管组织、星形胶质细胞和小胶质细胞反应以及神经退行性疾病的CSF生物标志物，提供了 研究神经元-小胶质细胞-星形胶质细胞相互作用对AD相关病理的反应的机会。我们提出 深入分析AppSAA小鼠神经元、小胶质细胞、星形胶质细胞和全脑组织的蛋白质组 在不同的年龄，利用我们新开发的邻近标记和传统的流式细胞术方法。 该项目的成功结果将确定新的、细胞类型特定的分子成分和途径 调节AD发病过程中的细胞-细胞相互作用，这可能为AD的治疗提供新的策略。 有效治疗这种毁灭性的疾病。