The most significant stroke risk factor is age. Age is also the most significant risk factor for Alzheimer's disease (AD). Amyloid deposition in the brain parenchyma and cerebral vasculature occurs in normal aging and in particular in AD. Amyloid deposition in the cerebral vasculature is a major cause of hemorrhagic and ischemic strokes in the elderly with or without AD. The major component of amyloid deposits in the cerebral vasculature is a small peptide, amyloid B (A,B). AB is cytotoxic to cerebral endothelial cells (CECs) in culture and in vivo. This effect of A,8 may contribute to the age-dependent development of cerebral amyloid angiopathy (CAA). The molecular mechanisms of AB cytotoxicity in CECs have not been fully elucidated. We have recently noted that A,8 stimulates ceramide synthesis in CECs probably by activating neutral sphingomyelinase (nSMase). Ceramide, a pro-apoptotic lipid mediator, is also cytotoxic to CECs. A,B and ceramide actions share certain apoptotic pathways that are triggered by mitochondrial dysfunction. These findings raise the possibility of the following cascade in AB cytotoxicity in CECs: AB - nSMase activation- increased ceramide synthesis - mitochondrial dysfunction - CEC apoptosis. The objectives of this project are to test the central hypothesis that AB cytotoxicity in CECs is at least partly mediated by ceramide following nSMase activation and the subsequent initiation of apoptotic processes due to mitochondrial dysfunction. The ultimate goal of this project is to develop therapeutic strategies to delay amyloid induced cerebrovascular degeneration by blocking the AB-ceramide cascade and the downstream apoptotic processes originating from mitochondria.

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-1 (01))
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Jacobs, Tom P
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Washington University
Schools of Medicine
Saint Louis
United States
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