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 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-beta peptide (Abeta) 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.
Park
Laibaik
L
Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
Zhou
Ping
P
Pitstick
Rose
R
Capone
Carmen
C
Anrather
Josef
J
Norris
Erin H
EH
Younkin
Linda
L
Younkin
Steven
S
Carlson
George
G
McEwen
Bruce S
BS
Iadecola
Costantino
C
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001526:Behavioral Symptoms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005609:Free Radicals / Q000009:adverse effects / Q000378:metabolism*; D006801:Humans; D006940:Hyperemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D005609:Free Radicals; D008562:Membrane Glycoproteins; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases