Mechanisms underlying Sex differences in Cerebral Amyloid Angiopathy: The Fibrin-Microglia Crosstalk

PROJECT SUMMARY/ ABSTRACT Cerebral amyloid angiopathy (CAA) is an Alzheimer's disease related dementia (ADRD) that has a high mortality and disability burden. 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. Interestingly, Alzheimer's disease (AD), a disease in which amyloid deposits are found predominantly in the brain parenchyma rather than in 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. We and others have found sex differences in mouse models of CAA across the lifespan. We have found that the fibrinolytic and inflammatory pathways are sexually dimorphic in mouse models of CAA. The focus of this project will be on fibrinogen, which is known to accumulate at sites of amyloid deposition, and activates microglia, leading to inflammation, microbleeds, fibrosis and further cognitive decline. In this proposal, we will use mice with genetic deletion of fibrinogen to determine the contributions of fibrin induced inflammation in CAA. We will also use pharmacological inhibition of fibrin/fibrosis in mice with CAA using the drug Pirfenidone, which is currently approved for use in patients with pulmonary fibrosis. By using genetic and pharmacological manipulation, we will examine the complex interaction of fibrin with microglia and it's downstream inflammatory pathways. We will also study the effect of this interaction on cognition, number of microbleeds and amyloid burden in the brain at different ages in both males and females. This will be the first step in understanding the complex interactions of these pathways with sex and age in CAA progression. This work will fill the gap in our understanding of the underlying mechanisms of sex differences in CAA pathology and vascular dementia and may lead to the development of sex specific therapies for this devastating disease.