Alzheimer's disease (AD) is a debilitating, chronic neurodegenerative disease that is the most common form of dementia. The pathophysiology of AD includes the progressive loss of neurons and synapses throughout the cerebral cortex as well as subcortical regions, and is characterized by the buildup of amyloid-beta (A?) plaques and tau-containing neurofibrillary tangle pathologies throughout these regions. A? plaques have been reported to be associated with neuronal and glial cells (parenchymal plaques), or associated with blood vessels (vascular plaques termed cerebral amyloid angiopathy [CAA]). CAA is found in up to 90% of patients with AD, and is thought to lead to impaired blood flow, altered vascular morphology, inflammation, microbleeds and hemorrhage. Despite the importance of CAA, very little is known about how A? deposits around vessels. There are two main hypotheses: First, vascular plaques are generated through the aberrant secretion of A? by endothelial cells and/or mural cells. Second, vascular plaques are generated though dysfunction in clearance of A?. Here we test a novel hypothesis: perivascular fibroblasts secrete A? in the generation of CAA. Work in our lab has identified that perivascular fibroblasts are intimately associated with vascular A? plaques in AD postmortem tissue. We have also identified that that perivascular fibroblasts robustly express amyloid precursor protein (APP) and the enzymes that process amyloid (BACE1/2, PSEN1). Here, we will use a conditional knockout approach to determine whether fibroblasts are the key cell type that secretes A? in the generation of CAA in a well characterized mouse model of AD. We will also utilize single cell sequencing to examine the cellular heterogeneity and gene expression of the perivascular fibroblasts as a function of time in the mouse AD model. If we find that perivascular fibroblasts are key contributors to A? secretion in the buildup of CAA, then this analysis will give insights into to the mechanism that leads to this vascular A? accumulation. If we find that fibroblast secretion of A? is not necessary for the generation of CAA, this analysis will provide vital information about how the fibroblasts change during the formation of vascular A? plaques, with which they are intimately associated.

Public Health Relevance

Alzheimer's disease (AD) is a debilitating chronic neurodegenerative disease that is characterized by the buildup of amyloid plaques in the central nervous system. These plaques can be associated with neuronal and glial cells (parenchymal plaques), or associated with blood vessels (vascular plaques termed Cerebral Amyloid Angiopathy), however very little is known about how vascular plaques are formed. Here we aim to examine the hypothesis that perivascular fibroblasts deposit amyloid in the generation of vascular plaques, and will further examine the gene expression of these cells in health and AD models.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Mackiewicz, Miroslaw
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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