Sexual Dimorphism in Cerebral Amyloid Angiopathy and Vascular Dementia: Investigating the Role of Fibrinolytic System

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PROJECT SUMMARY/ ABSTRACT Cerebral amyloid angiopathy (CAA) is an Alzheimer's disease related dementia (ADRD). The deposition of amyloid around the blood vessels in the brain leads to CAA. CAA is characterized by small cortical microbleeds in the brain, which not only leads to devastating spontaneous intracerebral hemorrhages, but also contributes to vascular dementia in the elderly. Therefore, this disease has a high mortality and disability burden. Interestingly, Alzheimer's disease (AD), a disease in which amyloid deposits are found predominantly in the brain parenchyma rather than the cerebral blood vessels, has been increasingly recognized as a sexually dimorphic disease. In AD patients, women perform poorly on verbal memory tasks and have a faster cognitive decline compared to men. However, such differences are understudied in CAA, which shares a very similar disease pathology of amyloid deposition. Using mouse models of CAA, we will study potential sex differences in CAA across the lifespan. We will do this by studying cognition, MRI and amyloid burden in the brain at different ages. The goal is to understand the complex interactions of sex and age in CAA progression. Like in many other diseases, the mechanism of CAA pathology may differ in males and females. The fibrinolytic pathway is known to be involved in the clearance of amyloid in Alzheimer's disease. We have found this pathway is sexually dimorphic. Our focus will initially be on Plasminogen Activator Inhibitor 1 (PAI-1), which is an inhibitor of tissue plasminogen activator that activates plasminogen and assists in amyloid clearance. In this proposal, we will use pharmacological inhibition and mice with genetic deletion of PAI-1 to determine if PAI-1 is a viable sex specific drug target for CAA. This study aims to fill the gap in our understanding of the sexual dichotomies in CAA pathology and vascular dementia and assist in development of sex specific therapies.