Integrin regulation of vascular function in Alzheimer's disease

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT This project aims at understanding the molecular mechanisms governing vascular and blood brain barrier function in Alzheimer’s disease (AD), and their involvement in AD pathophysiology. AD research has recently identified vascular dysfunction as a central hallmark of the disease correlating with cognitive impairment, and actively mediating the neuroinflammatory and amyloid burden in pre-clinical models and patients. However, the molecular mechanisms regulating vascular disfunction in AD remains limited. We found that the integrin CD49a, highly expressed in endothelial cells and pericytes and induced by the transforming growth factor TGF, is associated with AD (genome wide associated studies) and that modulation of CD49a expression impact the pathophysiology of AD in a pre-clinical model. We therefore hypothesize that CD49a expression by blood endothelial cells regulates vascular function in AD, mediates the deleterious effects of TGFb on vascular amyloidosis and negatively contribute to AD pathophysiology and cognition. Guided by our preliminary data, we propose to address our hypothesis using the following aims: Aim1: Determine how CD49a regulates blood brain barrier function. Aim2: Test the relationship between TGFb and CD49a in endothelial cells. Aim 3: Test the contribution of endothelial CD49a in the pathophysiology of Alzheimer’s disease. Collectively, our proposed studies will have a broad impact by: a) decipher the cell specific role of CD49a in blood brain barrier function; b) identify CD49a has a downstream pathway for the deleterious effects of TGFb on vascular pathology in AD; c) assert the role of CD49a and vascular dysfunction in the pathophysiology of AD, and d) highlight the therapeutic potential of targeting CD49a in AD and other neurovascular disorders.