Impact of vascular apoE in aging and AD

PROJECT SUMMARY (APOE U19: Project 4) While the major function of apolipoprotein E (apoE) is to mediate the lipid transport, APOE genotype (APOE2, APOE3 and APOE4) significantly influences cognitive function and Alzheimer’s disease (AD) pathogenesis through multiple pathways. APOE is associated with not only amyloid-β (Aβ) pathology but also cerebrovascular function including blood-brain barrier integrity and cerebral blood flow. Given that cerebrovascular disturbance substantially contributes to cognitive decline in the elderly and that apoE is abundantly expressed in vascular mural cells (smooth muscle cells and pericytes) as well as astrocytes and microglia in the brain, the overall goal of Project 4 is to define how APOE genotype in vascular mural cells impacts the molecular mechanisms and pathways in the development of cerebrovascular dysregulations and cognitive decline during aging and AD. In Aim 1, we will utilize novel mouse models, in which human APOE2, APOE3, or APOE4 gene is expressed upon an excision of a loxp-flanked STOP cassette by vascular mural cell specific sm22α promoter driven Cre expression to determine the effects of vascular mural cell-specific expression of apoE isoforms on cerebrovascular function and brain cognition during aging. In Aim 2, we will define the impact of apoE isoform deletion in vascular mural cells on age-related cerebrovascular dysfunction and cognitive decline using novel APOE knock-in mice, in which murine Apoe is replaced with floxed APOE2, APOE3, or APOE4 gene. By crossing with sm22α-Cre mice, we will specifically delete individual apoE isoforms in vascular mural cells. In Aim 3, we will examine how vascular-specific expression or deletion of apoE isoforms in conditional mouse models affects AD-related phenotypes by breeding the vascular mural cell-specific apoE isoform expressing or knockout mice with amyloid model APP knockin mice (AppNL-F/NL-F). Using those unique mouse models, we will comprehensively investigate how apoE isoforms in vascular mural cells impact cerebrovascular function, glial phenotypes, neuroinflammation, neurodegeneration, brain cognition and amyloid pathology at different ages. In particular, the apoE properties in the mouse models will be analyzed by the Biochemistry and Structural Modeling Core (Core B). ApoE amounts, oxidation and/or glycation in the mice as well as other AD-rerated fluid biomarkers will be measured through the Biomarker Core (Core D). While neuropathology in the mice will be investigated in Neuropathology Core (Core C), a multi-Omics approach including proteomics, metabolomics, lipidomics and single cell RNA sequencing will be carried out through the Multi-Omics Core (Core F) and Bioinformatics, Biostatistics, and Data Management Core (Core G) to profile molecular phenotypes in these mouse models. Together, our innovative study should fill a critical void in our understanding of how apoE isoforms in cerebrovasculature impact cellular functions and brain homeostasis during aging and AD through synergistic interaction with Core B-G and comparative mouse model studies by Project 2 and Project 3.