application) The amyloid precursor protein (APP) is intimately involved in the pathogenesis of Alzheimer's disease (AD). Amyloid plaques, one of the hallmarks of AD, consist primarily of a fragment of APP, the Abeta peptide. Although Abeta is thought to play a critical role in the pathogenesis of AD, the mechanisms by which it exerts its deleterious effects remain unclear. Recent data in isolated arteries suggest that Abeta impairs vascular reactivity, an effect mediated by free radical-induced endothelial damage. However, it is not known whether endogenous Abeta affects endothelial cells in vivo, and, if so, whether the attendant endothelial dysfunction results in alterations of the mechanisms regulating the cerebral circulation and the permeability of the blood-brain barrier. The long-term goal of these studies is to attempt to define the contribution of vascular factors to the pathogenesis of AD. In the present proposal the investigator will begin by testing the hypothesis, supported by preliminary findings, that Abeta impairs cerebral endothelial function by producing free radicals and that such endothelial dysfunction leads to alterations in cerebrovascular regulation and blood-brain barrier transport. Transgenic mice overexpressing a mutated form of APP695 will be used to investigate the cerebrovascular actions of APP and Abeta in vivo. The reactivity of cerebral blood flow to pharmacological and physiological stimuli will be studied by laser-Doppler flowmetry in mice equipped with a cranial window. Cerebral glucose utilization and blood-brain barrier permeability will be determined autoradiographically. The applicant will determine whether endothelium-mediated cerebrovascular responses are altered in APP transgenics. The investigator will also establish whether the endothelial dysfunction also leads to alterations in blood-brain barrier permeability and endothelial ultrastructure. In other studies, the investigator will use double transgenics overexpressing both APP and the superoxide scavenging enzyme SOD1 to determine whether SOD1 abrogates the endothelial dysfunction produced by APP overexpression. Fourth, overexpression of wild-type APP, which produces substantially less Abeta than mutated APP, will be studied to determine whether the cerebrovascular dysfunction correlates with Abeta levels. These studies will expand our understanding of the biological effects of APP overexpression and constitute a necessary first step toward elucidating the contribution of vascular factors to the development and progression of AD.
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