Thursday, December 26, 2024
12/26/2024
PROJECT SUMMARY Alzheimer`s disease (AD) is a progressive degenerative disease of the brain, a dementing illness associated with early neurovascular changes and the accumulation of misfolded amyloid-ß (Aß) and tau in the brain. At present, no effective treatment is available to slow or halt the progression of AD. Hence, uncovering novel mechanisms that govern AD pathogenesis may advance the development of more effective therapeutic strategies to treat this devastating disease. Mounting evidence suggests that the accumulation and aggregation of Ab in brain parenchyma and cerebral blood vessels (CBVs) is a key event leading to other AD-related pathologies. Kinetic studies in patients with sporadic AD indicate that faulty Aß clearance, rather than Aß overproduction, is critical for accumulation and aggregation of Aß in brain. However, the molecular underpinnings of such Aß accumulation remain poorly understood. Our preliminary studies indicate that heparan sulfate (HS), a type of sulfated polysaccharide that critically mediates cell-cell and cell-matrix interaction and signaling, is strongly reduced in CBVs of AD patients. In this application, we will test our novel hypothesis that HS expressed in CBVs normally facilitates the clearance of Ab out of the brain and that such function is disrupted in AD, leading to impaired Ab clearance. Mechanistically, we hypothesize that HS maintains CBV integrity, functions as a co-receptor in LRP1-mediated Ab clearance and facilitates perivascular Ab elimination. We will pursue the following 3 specific aims to rigorously test our hypothesis: 1. Elucidate the roles of brain endothelial cell (bEC) HS in Ab clearance and test the hypothesis that increasing bEC-HS expression normalizes Ab clearance to mitigate AD pathogenesis. 2. Delineate the molecular mechanisms underlying the roles of bEC-HS in brain Ab clearance and AD pathogenesis. 3. Elucidate the roles of brain vascular smooth muscle cell (bVSMC)- HS in brain Ab clearance and AD pathogenesis. These proposed studies exploit both novel and established genetic, cellular, scRNA-seq and biochemical approaches in conjunction with human AD specimen and AD mouse models. The results of this study are expected to illuminate HS expressed in CBVs serves as a key molecule to mediate brain Ab clearance and decreased CVS-HS expression exacerbates AD, and will provide in vivo evidence for the proof of principle that increasing bEC-HS is an effective intervention to mitigate AD pathogenesis.
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