Brain capillaries are composed of a single layer of endothelial cells covered by specialized mural cells called pericytes. Communication between pericytes and endothelial cells is essential for brain capillary health. Recent studies indicate that Alzheimer?s disease and vascular dementia involve increased death or degeneration of brain pericytes. This is thought to contribute to the impairment of both blood-brain barrier integrity and cerebral blood flow, which subsequently exacerbates neurodegeneration. Therefore, strategies to mitigate or compensate for loss of pericyte coverage may help to preserved vascular function in these neurological diseases. We recently discovered that brain pericytes have the ability to structurally remodel in the adult brain. In response to focal ablation of single pericytes in vivo, we observed the robust extension of processes from neighboring pericytes, which could reach over large stretches of capillary bed to regain contact with the exposed endothelium. In young healthy mice, the transient loss of pericyte coverage led to persistent capillary dilation and abnormally high blood cell flux, until pericyte contact was regained. These findings suggest that pericyte remodeling is a reparative mechanism to compensate for pericyte loss. We hypothesize that this capacity is diminished with age and further impaired with amyloid deposition during cerebral amyloid angiopathy, a frequent small vessel disease in Alzheimer?s. To address this hypothesis, we plan to use in vivo two-photon microscopy to directly observe pericytes dynamics in normal mice and mice with cerebral amyloid angiopathy.
In Aim 1, we will test whether remodeling capacity is reduced in young and aged Tg-SwDI mice, which exhibit a unique enrichment of capillary amyloid deposits over time.
In Aim 2, we will use a novel oxygen-sensitive probe designed for two-photon imaging to better understand the consequence of pericyte loss on blood flow and local tissue oxygenation. This project will shed light on a largely unstudied facet of pericyte biology that may lead to novel approaches to augment pericyte-endothelial contact and preserve brain capillary health in Alzheimer?s disease. It will advance the field by: 1) Characterizing the dynamics of pericyte remodeling in detail using in vivo optical imaging, 2) providing insight on how small vessel disease impairs the reparative capacity of brain capillaries, and 3) promoting the development of new tools to study pericytes with unprecedented specificity in the living mouse brain.
Alzheimer?s disease creates an enormous socioeconomic burden in the United States and basic research is urgently needed to identify therapeutic targets for better treatment. This preclinical project focuses on a vascular cell type called a pericyte that is uniquely vulnerable to injury and contributes to Alzheimer?s disease progression by impairing the brain?s vascular system. We will use cutting-edge microscopy in the live mouse brain to study how the brain?s vascular system is repaired after pericyte loss, yielding novel insight into strategies for vascular protection.
