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? leads to inflammatory responses, compromised A? 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?, its mechanism and elaboration. An A?-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? clearance through receptor-mediated internalization, and to elucidate mechanisms for A? 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. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-L (90))
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Jacobs, Tom P
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Sun Health Research Institute
Sun City
United States
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Xiong, Huaqi; Callaghan, Debbie; Jones, Aimee et al. (2009) ABCG2 is upregulated in Alzheimer's brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood-brain barrier for Abeta(1-40) peptides. J Neurosci 29:5463-75
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