Grant: Project Grant

To date, Alzheimer disease (AD) research has primarily focused on conversion of the amyloid precursor protein into the aggregation prone amyloid-beta 42 (Abeta42) peptide which can stick together to form amyloid plaques in the brain. Clinically, the ratio between soluble Abeta40 and Abeta42 peptides indicates whether the stage of disease progression is mild, moderate, or severe (soluble Abeta42 decreases in patient body fluids as it becomes deposited as plaques). Distinct from the Abeta42 imbalances in AD patients, we have preliminary evidence suggesting that the atypical aggregation of soluble Abeta40 may contribute to the development of sporadic cerebral amyloid angiopathy (CAA). CAA is a neurological disease in which Abeta40 sticks to blood vessels, prompting memory problems and strokes due to bleeding in the brain. Recent studies suggest that CAA and AD are caused by decreased Abeta clearance which leads to increased deposition of amyloid plaques. Ultimately, we propose that atypical levels of Abeta40 deposition during the pre-symptomatic stages of CAA are due to impaired clearance mechanisms. To better understand the dynamic balance between the production and clearance of Abeta species in the genesis of both sporadic and inherited forms of CAA, our project will examine the role of specific amyloid peptides in CAA-relevant human cells and tissues.