Abeta-induced vascular oxidative stress and attenuation of functional hyperemia in mouse somatosensory cortex.
We investigated the role of vascular oxidative stress in the mechanisms of the impairment in cerebrovascular regulation produced by the amyloid-beta peptide (Abeta). In particular, we sought to provide evidence of vascular oxidative stress in mice overexpressing the amyloid precursor protein (APP) and to determine whether the Abeta-induced attenuation in functional hyperemia is mediated by free radical overproduction. Oxidative/nitrosative stress was assessed by 3-nitrotyrosine immunoreactivity, while free radical production was determined in cerebral microvessels by hydroethidine microfluorography. To study functional hyperemia the somatosensory cortex was activated by whisker stimulation while local blood flow was monitored by laser-Doppler flowmetry. It was found that APP mice show signs of oxidative/nitrosative stress in pial and intracerebral blood vessels well before they develop oxidative stress in neurons and glia or amyloid plaques. Treatment of cerebral microvessels isolated from wild-type mice with Abeta (1 microM) increased free radical production as assessed by the hydroethidine technique. The Abeta-induced attenuation of the increase in somatosensory cortex blood flow produced by whisker stimulation was prevented by treatment with the free radical scavengers MnTBAP or tiron. These data provide evidence that in APP mice vascular oxidative stress precedes the development of parenchymal oxidative stress, and that Abeta-produced vascular reactive oxygen species are involved in the attendant attenuation in functional hyperemia. Thus, vascular oxidative stress is an early event in the course of the brain dysfunction produced by APP overexpression and Abeta, and, as such, could be the target of early therapeutic interventions based on antioxidants.
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
Forster
Colleen
C
Kazama
Ken
K
Carlson
George A
GA
Iadecola
Costantino
C
D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology*; D016166:Free Radical Scavengers / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D006940:Hyperemia / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism; D010812:Physical Stimulation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012039:Regional Blood Flow; D013003:Somatosensory Cortex / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016166:Free Radical Scavengers; D005609:Free Radicals; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C002744:3-nitrotyrosine; D014443:Tyrosine