Alzheimer's disease (AD) is a devastating chronic neurodegenerative disease and the leading cause of dementia in older adults. One of the hallmark pathologies of AD is accumulation of extracellular amyloid-beta (A?) ?plaques?. These plaques can form both in the parenchyma as well as in the walls of meningeal and cerebral blood vessels. Vascular A? plaques, termed cerebral amyloid angiopathy (CAA), are present in up to 98% of AD patients and can cause stroke, dementia, inflammation, cortical microbleeds, and hemorrhage. Despite the serious clinical ramifications of CAA, it remains unclear why plaques develop in vascular walls. With therapeutic prevention of CAA as a long-term goal, this proposal aims to investigate the role of microglia in regulating cholesterol homeostasis in endothelial cells (ECs)??the cells that make up the walls of blood vessels. There are several epidemiological links between cholesterol and AD, yet the specific mechanisms underlying this association are unknown. Our preliminary data show that microglial depletion causes upregulation of cholesterol synthesis enzymes in brain ECs. Because a higher cellular levels of esterified cholesterol have been shown to increase A? production, we hypothesize that microglial dysfunction in AD disrupts brain EC cholesterol metabolism, driving A? production and secretion, thereby potentiating CAA in AD. This proposal will test this novel hypothesis and will also determine how dietary cholesterol modulates brain EC cholesterol metabolism. Specifically, we will test how microglial depletion affects cholesterol synthesis in other neural cell types by quantifying expression of cholesterol synthesis machinery in astrocytes, neurons, and oligodendrocytes. As brain ECs lie at the interface between the brain and the blood, we will also investigate how increasing dietary cholesterol with a high fat diet modulates cholesterol metabolism in brain ECs. Finally, we will assess the separate and combined effects of microglial depletion and high fat diet on vascular pathology in a model of AD. Taken together, the experiments proposed here will advance our understanding of the association between cholesterol and AD, particualrly CAA. Furthermore, these data will identify whether therapeutic regulation of cholesterol synthesis or efflux specifically in brain ECs could be a successful clinical strategy for preventing CAA.
Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by the buildup of amyloid plaques in the brain, which can be associated with neuronal and glial cells or with blood vessels. Vascular plaques, termed cerebral amyloid angiopathy (CAA), have serious clinical ramifications including dementia, stroke, microbleeds, and hemorrhage. The proposed project will investigate the role of cerebrovascular cholesterol homeostasis in CAA with the goal of identifying a new therapeutic target for the prevention of vascular pathology in AD.
