Inflammation, Abeta, and pericyte pathogenic roles

Sun Health Research Institute, Sun City AZ

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Our objective is to use a unique human primary culture model to define the molecular pathogenic mechanisms of brain pericytes in microvasculature of Alzheimer's disease (AD). This is one important step towards our long-term goal, which is to gain better understanding on how AD vascular dysfunction evolves and to establish a cause-and-effect relationship between vascular pathology and neurodegeneration. Vascular inflammation, microvascular dysfunction, and cerebral amyloid angiopathy characterize vascular pathology in AD. We propose that pericytes, which modulate multi-facets of BBB functions, contribute to these abnormalities. Our central hypothesis is that activation of brain pericytes by A[unreadable] leads to inflammatory responses, compromised A[unreadable] clearance, and disturbed BBB functions, and these effects could be exaggerated by hypoxic and inflammatory conditions and ameliorated by anti-inflammatory treatments. Aim 1 is to investigate receptor-mediated cellular activation by A[unreadable], its mechanism and elaboration. An A[unreadable]-binding cell surface receptor, receptor for advanced glycation endproducts (RAGE), will be tested for its role in inducing and perpetuating inflammatory responses and cellular stress. Aim 2 is to investigate pericytemediated A[unreadable] clearance through receptor-mediated internalization, and to elucidate mechanisms for A[unreadable] accumulation. We hypothesize that activation of pericytes impairs clearance mechanism and promotes accumulation. Aim 3 is to investigate how activated pericytes perturb endothelial BBB function and angiogenic process. Endothelial cells, pericytes, and astrocytes isolated from the same autopsy cases will be co-cultured for modeling these changes. The outcome of this study will improve our understanding in pericyte-driven molecular and cellular mechanisms in the formation of cerebral amyloid angiopathy and vascular inflammation at the blood brain barrier and will provide insights to vascular pathogensis in AD. [unreadable] [unreadable]