NADPH oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid β peptide

Laibaik Park, Josef Anrather, Ping Zhou, Kelly Frys, Rose Pitstick, Steven G Younkin, George A. Carlson, Costantino Iadecola

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

Overproduction of the amyloid β(Aβ) 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 Aβ 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 Aβ. Thus, the free-radical production and the associated alterations in vasoregulation induced by Aβ 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 gp91 phox-containing NADPH oxidase is the critical link between Aβ and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD patients.

Original languageEnglish (US)
Pages (from-to)1769-1777
Number of pages9
JournalJournal of Neuroscience
Volume25
Issue number7
DOIs
StatePublished - Feb 16 2005

Fingerprint

NADPH Oxidase
Amyloid
Reactive Oxygen Species
Peptides
Alzheimer Disease
Free Radicals
Blood Vessels
Cerebrovascular Circulation
Amyloid beta-Protein Precursor
Transgenic Mice
Biological Availability
Catalytic Domain
Nitric Oxide
Oxidative Stress

Keywords

  • Alzheimer's disease
  • Cerebral blood flow
  • gp91
  • Hydroethidine
  • Reactive oxygen species
  • Tg2576

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

NADPH oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid β peptide. / Park, Laibaik; Anrather, Josef; Zhou, Ping; Frys, Kelly; Pitstick, Rose; Younkin, Steven G; Carlson, George A.; Iadecola, Costantino.

In: Journal of Neuroscience, Vol. 25, No. 7, 16.02.2005, p. 1769-1777.

Research output: Contribution to journalArticle

Park, Laibaik ; Anrather, Josef ; Zhou, Ping ; Frys, Kelly ; Pitstick, Rose ; Younkin, Steven G ; Carlson, George A. ; Iadecola, Costantino. / NADPH oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid β peptide. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 7. pp. 1769-1777.
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