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The Journal of Neuroscience, February 16, 2005, 25(7):1769-1777; doi:10.1523/JNEUROSCI.5207-04.2005

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Neurobiology of Disease
NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid Peptide

Laibaik Park,¹ Josef Anrather,¹ Ping Zhou,¹ Kelly Frys,¹ Rose Pitstick,³ Steven Younkin,² George A. Carlson,³ and Costantino Iadecola¹

¹Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, ²Mayo Clinic Jacksonville, Jacksonville, Florida 32224, and ³McLaughlin Research Institute, Great Falls, Montana 59405

Overproduction of the amyloid (A) peptide is a key factor in the pathogenesis of Alzheimer's disease (AD), but the mechanisms of its pathogenic effects have not been defined. Patients with AD have cerebrovascular alterations attributable to the deleterious effects of A on cerebral blood vessels. We report here that NADPH oxidase, the major source of free radicals in blood vessels, is responsible for the cerebrovascular dysregulation induced by A. Thus, the free-radical production and the associated alterations in vasoregulation induced by A are abrogated by the NADPH oxidase peptide inhibitor gp91ds-tat and are not observed in mice lacking the catalytic subunit of NADPH oxidase (gp91^phox). Furthermore, oxidative stress and cerebrovascular dysfunction do not occur in transgenic mice overexpressing the amyloid precursor protein but lacking gp91^phox. The mechanisms by which NADPH oxidase-derived radicals mediate the cerebrovascular dysfunction involve reduced bioavailability of nitric oxide. Thus, a gp91^phox-containing NADPH oxidase is the critical link between A and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD patients.

Key words: Alzheimer's disease; hydroethidine; gp91^phox; Tg2576; cerebral blood flow; reactive oxygen species

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Received Dec 21, 2004; revised January 6, 2005; accepted January 8, 2005.

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