NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide.
Overproduction of the amyloid beta (Abeta) 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 Abeta 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 Abeta. Thus, the free-radical production and the associated alterations in vasoregulation induced by Abeta are abrogated by the NADPH oxidase peptide inhibitor gp91ds-tat and are not observed in mice lacking the catalytic subunit of NADPH oxidase (gp91phox). Furthermore, oxidative stress and cerebrovascular dysfunction do not occur in transgenic mice overexpressing the amyloid precursor protein but lacking gp91phox. The mechanisms by which NADPH oxidase-derived radicals mediate the cerebrovascular dysfunction involve reduced bioavailability of nitric oxide. Thus, a gp91phox-containing NADPH oxidase is the critical link between Abeta and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD patients.
Park
Laibaik
L
Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
Anrather
Josef
J
Zhou
Ping
P
Frys
Kelly
K
Pitstick
Rose
R
Younkin
Steven
S
Carlson
George A
GA
Iadecola
Costantino
C
D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002560:Cerebrovascular Circulation; D005260:Female; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D006940:Hyperemia / Q000209:etiology; D017078:Laser-Doppler Flowmetry; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000633:toxicity*; D010617:Phenanthridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014738:Vibrissae / Q000502:physiology; D014960:X Chromosome / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D020030:Nitric Oxide Donors; D010446:Peptide Fragments; D010617:Phenanthridines; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C093598:amyloid beta-protein precursor 695 (681-695); C473031:gp91ds-tat protein, chimeric; D000001:Calcimycin; C058428:hydroethidine; D026423:S-Nitroso-N-Acetylpenicillamine; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000241:Adenosine; D000109:Acetylcholine; D001920:Bradykinin
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