National Institute on Aging 5R00AG080034-04

Exploring brain perivascular fibroblasts in health and cerebral amyloid angiopathy

This NIH-funded project investigates the role of brain perivascular fibroblasts (PVFs) in maintaining arteriole structure and dynamics, particularly in the context of cerebral amyloid angiopathy (CAA) and Alzheimer's Disease (AD). The research aims to understand how PVF loss affects vascular integrity and contributes to disease pathology, potentially leading to new therapies to improve brain vascular health.

Description

Maintaining a stable brain vascular network is crucial for ensuring overall brain health throughout life. Perivascular cells, like pericytes and smooth muscle cells, are crucial to maintain the integrity of the brain vasculature. Loss of pericytes and smooth muscle cells are noted in Alzheimer’s Disease (AD) and affects vascular integrity, ultimately contributing to disease pathology. Perivascular fibroblasts (PVFs) are another cell population along the brain vasculature, however their role is largely unknown. PVFs express numerous extracellular matrix proteins that are uniquely found on arterioles and venules but not capillaries. Preliminary investigations indicate that PVFs maintain vessel structural stability, particularly along arterioles, in the healthy brain. Further, arterioles are more tortuous in a mouse model of cerebral amyloid angiopathy (CAA), and this is associated with a significant reduction in PVFs. CAA is a small vessel disease characterized by the accumulation of amyloid-β on vessels commonly observed in AD. Arterioles and their immediate off-shoots are important major regulators of blood flow into the brain. They undergo extensive dilation and constriction events which are likely supported in part by extracellular matrix proteins expressed by PVFs. The goal of this project is to determine if PVFs regulate arteriole structure and dynamics in the healthy brain and to understand if CAA contributes to PVF loss, altering arteriole structure and dynamics by affecting the expression of extracellular matrix proteins, ultimately exacerbating CAA. Understanding these aspects could lead to therapeutics aimed at limiting AD pathology and improving vascular function.

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