Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein

Alterations in cerebrovascular regulation related to vascular oxidative stress have been implicated in the mechanisms of Alzheimer's disease (AD), but their role in the amyloid deposition and cognitive impairment associated with AD remains unclear. We used mice overexpressing the Swedish mutati...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-01, Vol.105 (4), p.1347-1352
Main Authors: Park, Laibaik, Zhou, Ping, Pitstick, Rose, Capone, Carmen, Anrather, Josef, Norris, Erin H, Younkin, Linda, Younkin, Steven, Carlson, George, McEwen, Bruce S, Iadecola, Costantino
Format: Article
Language:English
Subjects:
Alzheimer's disease
Alzheimers disease
Amino Acid Sequence
Amyloid beta-Protein Precursor - biosynthesis
Amyloid beta-Protein Precursor - genetics
Amyloids
Animals
Behavioral Symptoms - genetics
Behavioral Symptoms - metabolism
Behavioral Symptoms - physiopathology
Biochemistry
Biological Sciences
Brain
Brain - blood supply
Brain - metabolism
Brain - physiopathology
Carbohydrates
Cerebrovascular Circulation - genetics
Disease Models, Animal
Female
Free Radicals - adverse effects
Free Radicals - metabolism
Humans
Hyperemia
Hyperemia - genetics
Hyperemia - metabolism
Hyperemia - physiopathology
Male
Maze Learning - physiology
Membrane Glycoproteins - antagonists & inhibitors
Membrane Glycoproteins - biosynthesis
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Molecular Sequence Data
NADPH Oxidase 2
NADPH Oxidases - antagonists & inhibitors
NADPH Oxidases - biosynthesis
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
Neurosciences
Oxidases
Oxidative stress
Protein precursors
Proteins
Reactive oxygen species
Rodents
Transcriptional regulatory elements
Transgenic animals
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Description
Summary:Alterations in cerebrovascular regulation related to vascular oxidative stress have been implicated in the mechanisms of Alzheimer's disease (AD), but their role in the amyloid deposition and cognitive impairment associated with AD remains unclear. We used mice overexpressing the Swedish mutation of the amyloid precursor protein (Tg2576) as a model of AD to examine the role of reactive oxygen species produced by NADPH oxidase in the cerebrovascular alterations, amyloid deposition, and behavioral deficits observed in these mice. We found that 12- to 15-month-old Tg2576 mice lacking the catalytic subunit Nox2 of NADPH oxidase do not develop oxidative stress, cerebrovascular dysfunction, or behavioral deficits. These improvements occurred without reductions in brain amyloid-β peptide (Aβ) levels or amyloid plaques. The findings unveil a previously unrecognized role of Nox2-derived radicals in the behavioral deficits of Tg2576 mice and provide a link between the neurovascular dysfunction and cognitive decline associated with amyloid pathology.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0711568105