Defining the cell-autonomous role of caveolin-1 in adult hippocampal neurogenesis in Alzheimer's Disease

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PROJECT SUMMARY/ABSTRACT: Over 95% of Alzheimer’s Disease (AD) cases worldwide are sporadic, late onset (LOAD) affecting individuals age 65 years or older. One of the earliest clinical symptoms of AD is impairment in hippocampus-dependent memory. Throughout life, the hippocampus notably maintains a pool of neural stem and progenitor cells (NSCs/NPCs) that differentiate into granule cell neurons (GCs) through the process of adult hippocampal neurogenesis (AHN). AHN is imperative for hippocampal plasticity and memory function as newly born GCs are recruited in memory engram cells. It is well-known that AHN is impaired in mouse models of AD and augmentation of AHN in AD mice rescues hippocampus-dependent memory function. However, the mechanisms underlying compromise in AHN in AD are not clear. Caveolin-1 (Cav-1) is a scaffolding protein abundant in endothelial caveolae. We and others have shown that reductions in Cav-1 expression in the hippocampus induce AD-like pathology and memory deficits. Preliminary studies in our lab show that AHN is impaired in a global Cav- 1 knockout mouse and restoration of endothelial Cav-1 in this model does not restore the pool of NSCs suggesting a novel autonomous role of Cav-1 in AHN. Importantly, my preliminary results show that cell- autonomous deletion of Cav-1 in hippocampal NSCs/NPCs compromises expression of critical AD-linked proteins including amyloid precursor protein, β-secretase (BACE-1) and phosphatidylinositol binding clathrin assembly protein (PICALM), a genetic risk factor of late onset AD. This project will examine the hypothesis that Cav-1 regulates AHN in a cell-autonomous manner and that altered expression of neurogenic Cav-1 in AD may underlie deficits in neurogenesis. Utilizing a newly generated mouse model harboring conditional deletion of Cav-1 in NSCs (NestinCreERT2;Cav- 1lox/lox), studies in Aim 1 will establish the cell-autonomous role of Cav-1 in AHN. Aim 2 will elucidated the fate of Cav-1 in hippocampal NSCs/NPCs derived from two AD models, APPswePS1ΔE9 and APPKINL-G-F/NL-G-F, and determine how Cav-1 regulates expression and membrane lipid raft localization of AD-linked protein and phenotype of hippocampal NSCs/NPCs in AD. Taken together, this project will provide imperative insight into Cav-1 as an novel and essential regulator of AHN and establish whether alterations in Cav-1 contribute to impairments in hippocampal NSCs/NPCs function in AD. This project implies that restoring Cav-1 level in AHN may help attenuate memory deficits in AD.