Project 3: Astrocytic and microglial apoE in aging and AD

Project 3 seeks to elucidate whether different isoforms of astrocytic and microglial apoE exhibit different biochemical properties that impact its function, aggregation, and the metabolism of amyloid-β (Aβ) during aging and AD development.

Using novel inducible mouse models in which human APOE2, APOE3, or APOE4 gene is specifically expressed in astrocytes or microglia as well as using innovative technologies (ie. in vivo 2-photon imaging and in vivo microdialysis), we will address whether apoE isoform-mediated microglia- astrocyte interaction affects brain functions and amyloid pathologies. More importantly, multi-disciplinary approaches will be employed by interacting with other projects/cores: 1) The properties of apoE particles from our mouse models will be analyzed by Project 1 and Core B; 2) ApoE amounts and AD-related fluid biomarkers will be measured through Core D; 3) The amyloid pathologies and neuroninflammation will be examined by Core C; 4) The molecular phenotypes of our inducible apoE mouse models will be examined using multi-omics approaches (ie., proteomics, metabolomics, lipidomics and single cell RNA sequencing), with results correlating with human studies through Cores F, G; 5) Our data can be compared with studies from Projects 2 and 4 to further elucidate the cell type-specific effects; and 6) Findings from mouse models can be further validated using human iPSC-derived microglia/astrocyte models in Core E.

Project 3 Principal Investigators