Dissecting neuron-microglia-astrocyte interaction in AD pathogenesis

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.