OVEREXPRESSION OF APR AND CEREBROVASCULAR REGULATION Alzheimer's disease (AD), the major cause of dementia in the elderly, is characterized pathologically by accumulation in brain of amyloid-ft (Aft), a peptide derived from the proteolytic cleavage of the amyloid precursor protein. A growing body of evidence indicates that Aft induces profound alterations in the regulation of the cerebral circulation that are thought to play a pathogenic role in AD. However, relatively little is known about the mechanisms by which Aft acts on cerebral blood vessels to disrupt their function. Studies over the previous funding period have provided evidence that the cerebrovascular dysfunction induced by Aft is mediated by superoxide produced in cerebrovascular cells by the enzyme NADPH oxidase. The goal of this renewal application is to provide insight into the cell surface receptors through which Aft activates NADPH oxidase and the downstream mechanisms by which the resulting free radical production alters cerebrovascular regulation. In particular, we will test the hypotheses that the scavenger receptor CD36 is essential for the NADPH oxidase-dependent superoxide production induced by Aft, and that peroxynitrite formed by superoxide and nitric oxide, leads to vascular nitrosative stress, which in turn, disrupts cerebrovascular function through excessive activation of the DNA repair enzyme polv(ADP)ribose polymerase. Studies will be conducted in wild-type mice and in mice overexpressing the amyloid precursor protein, a model of AD. Cerebral blood flow and its regulation will be investigated using a cranial window preparation. The role of CD36, peroxynitrite, and poly(ADP)ribose polymerase will be tested using neuroanatomical, biochemical, and pharmacological approaches, as well as genetically engineered mice. The proposed studies will expand our understanding of the biological processes underlying the cerebrovascular alterations induced by Aft and may provide the preclinical bases for novel preventive and treatment strategies for AD and related conditions associated with Aft overproduction. ? ? ?
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