Elucidating the Temporal, Spatial and Cellular Effects of Differential APOE Isoform Expression

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Project Summary Carriers of the apolipoprotein E (APOE) ε4 gene are at a significantly increased risk for developing Alzheimer’s disease (AD). Although numerous theories have been proposed, the cause of this association remains unclear. My own research has uncovered novel effects of APOE4 expression on important processes in the brain, including neuronal activity, the endosomal-lysosomal system and bioenergetic regulation. However, substantial questions remain about when, where and how these systems are effected by differential APOE isoform expression. In order to answer these questions and gain a more comprehensive understanding of how differential APOE isoform expression affects vital brain processes and pathways, I propose a series of cutting-edge experiments, performed on a newly created APOE mouse model. By conducting behavioral experiments, histological examinations, imaging and an array of spatial multi-omics experiments, this project aims to define the temporal, spatial and cellular progression of differential APOE isoform effects in the brain. Each of these experiments will be performed on young (4-6 month-old), aged (14-16 month-old), and old (24-26 month-old) APOE2, APOE3 and APOE4-KI mice. In Aim 1, we will conduct a series of behavioral tests, including Barnes maze, novel object recognition, and fear conditioning, as well as a histological analysis for endosomal-lysosomal disruptions, bioenergetic deficits, and changes in AD pathology markers. We will also conduct a detailed imaging analysis using fMRI to observe activity and structural changes in these mice. In Aim 2, we will conduct an in- depth spatial multi-omics analysis on these mice, including spatial transcriptomics and spatial metabolomics/lipidomics. And in Aim 3, we will explore the cellular contributions to differential APOE isoform expression, including a novel bioinformatics approach and conditionally knockout of APOE from astrocytes and microglia in the APOE-KI mice. We anticipate that the full study proposed herein will uncover important APOE isoform effects on multiple brain processes and pathways in a systems-biology manner, which will dramatically increase our understanding of how APOE isoform differences affect an individual’s susceptibility to AD, potentially leading to new therapeutic strategies for AD, especially among APOE4 carriers.