Monday, May 12, 2025
5/12/2025
PATHOBIOLOGICAL STUDIES OF VESSEL BACE1 IN CEREBROVASCULAR AMYLOID ANGIOPATHY - Abstract The incidence of Alzheimer disease (AD) with vascular degeneration is greatly increased following cerebral hemorrhagic stroke in which cerebral amyloid angiopathy (CAA) occurs in affected brain areas. The most common form of CAA is of the amyloid beta-peptide (Aβ) type. Aβ, which is derived from the beta-amyloid precursor protein (APP) by sequential proteolytic cleavages from β-secretase (BACE1) and -secretase, is widely believed to trigger a cascade of pathological events culminating in AD including accompanied by degeneration of vascular cells: vascular smooth muscle cells (VSMCs), vascular endothelial cells (VENCs) and pericytes. While extensive studies on pericytes in CAA have been performed, multiple studies demonstrated that an increasing accumulation of A in the vessel basement membrane is associated with the degeneration of adjacent VSMCs and VENCs. Importantly, our recent preliminary data showed that cerebral vascular cells from human CAA brains express high levels of β-secretase (BACE1). However, what causes vascular degeneration or death in CAA remains unclear. We recently reported that a cell death receptor, TNFRI, is required for Aβ- induced cell death and depletion of TNFRI reduced BACE1. In this application, we will study whether and how BACE1 can be up-regulated in vascular cells and what molecular mechanisms of BACE1 elevation causes cerebral vascular cell death in our new mouse models of AD related CAA. The ultimate goal of this proposal will not only advance our understanding the mechanisms of CAA- induced hemorrhage but, also to, in principle, identify novel therapeutic targets and offer novel alert for potential side effects of BACE1 inhibitors in patients with Alzheimer’s disease accompanying vascular degeneration. Key words: BACE1, TNF inflammation, animal models, neurodegeneration
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