Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylcholine / pharmacology
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Adenosine / pharmacology
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Alzheimer Disease / metabolism
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Alzheimer Disease / physiopathology
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Amino Acid Sequence
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Amyloid beta-Peptides / biosynthesis
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Amyloid beta-Peptides / toxicity*
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Amyloid beta-Protein Precursor / biosynthesis
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Amyloid beta-Protein Precursor / genetics
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Animals
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Bradykinin / pharmacology
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Calcimycin / pharmacology
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Cerebrovascular Circulation
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Female
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Glycoproteins / pharmacology
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Humans
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Hyperemia / etiology
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Laser-Doppler Flowmetry
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Male
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Molecular Sequence Data
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NADPH Oxidase 2
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NADPH Oxidases / deficiency
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NADPH Oxidases / genetics
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NADPH Oxidases / physiology*
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Nerve Tissue Proteins / physiology*
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Nitric Oxide Donors / pharmacology
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Oxidative Stress
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Peptide Fragments / biosynthesis
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Peptide Fragments / genetics
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Peptide Fragments / toxicity*
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Phenanthridines / pharmacology
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Reactive Oxygen Species / metabolism*
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S-Nitroso-N-Acetylpenicillamine / pharmacology
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Vibrissae / physiology
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X Chromosome / genetics
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Glycoproteins
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Membrane Glycoproteins
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Nerve Tissue Proteins
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Nitric Oxide Donors
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Peptide Fragments
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Phenanthridines
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Reactive Oxygen Species
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amyloid beta-protein (1-40)
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amyloid beta-protein precursor 695 (681-695)
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gp91ds-tat protein, chimeric
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Calcimycin
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hydroethidine
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S-Nitroso-N-Acetylpenicillamine
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Cybb protein, mouse
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NADPH Oxidase 2
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NADPH Oxidases
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Adenosine
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Acetylcholine
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Bradykinin