Dissecting neuron-microglia-astrocyte interaction in AD pathogenesis

项目摘要/摘要 这项补助金补充的目的是研究神经元-小胶质细胞-星形胶质细胞相互作用的功能障碍。 在阿尔茨海默病(AD)的发病机制中，通过执行细胞类型特定的蛋白质组学图谱 一种新的阿尔茨海默病动物模型。最近，一款App敲入鼠标模型(APP-SAA Ki)被推出 生成表达带有三个家族突变的人源化APP：KM670/671NL(瑞典)，E693G(北极) 和T714I(奥地利语)。该模型显示了与AD相关的关键病理，包括大脑和大脑中的淀粉样斑块 血管组织、星形胶质细胞和小胶质细胞反应，以及神经退行性变的脑脊液生物标志物，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相关病理反应的机会。我们建议 对AppSAA小鼠的神经元、小胶质细胞、星形胶质细胞和整个脑组织的蛋白质组进行深入分析 在不同的年龄段，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 在AD发病过程中调节细胞间的相互作用，可能为AD的治疗提供新的策略 对这种破坏性疾病的有效治疗。

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.