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.