title: Vascular remodeling versus amyloid beta-induced oxidative stress in the cerebrovascular dysfunctions associated with Alzheimer's disease.
abstract: The roles of oxidative stress and structural alterations in the cerebrovascular dysfunctions associated with Alzheimer's disease (AD) were investigated in transgenic mice overexpressing amyloid precusor protein (APP+) or transforming growth factor-beta1 (TGF+). Age-related impairments and their in vitro reversibility were evaluated, and underlying pathogenic mechanisms were assessed and compared with those seen in AD brains. Vasoconstrictions to 5-HT and endothelin-1 were preserved, except in the oldest (18-21 months of age) TGF+ mice. Despite unaltered relaxations to sodium nitroprusside, acetylcholine (ACh) and calcitonin gene-related peptide-mediated dilatations were impaired, and there was an age-related deficit in the basal availability of nitric oxide (NO) that progressed more gradually in TGF+ mice. The expression and progression of these deficits were unrelated to the onset or extent of thioflavin-S-positive vessels. Manganese superoxide dismutase (SOD2) was upregulated in pial vessels and around brain microvessels of APP+ mice, pointing to a role of superoxide in the dysfunctions elicited by amyloidosis. In contrast, vascular wall remodeling associated with decreased levels of endothelial NO synthase and cyclooxygenase-2 and increased contents of vascular endothelial growth factor and collagen-I and -IV characterized TGF+ mice. Exogenous SOD or catalase normalized ACh dilatations and NO availability in vessels from aged APP+ mice but had no effect in those of TGF+ mice. Increased perivascular oxidative stress was not evidenced in AD brains, but vascular wall alterations compared well with those seen in TGF+ mice. We conclude that brain vessel remodeling and associated alterations in levels of vasoactive signaling molecules are key contributors to AD cerebrovascular dysfunctions.
authors.affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, H3A 2B4, Canada.
authors.forename: Xin-Kang
authors.initials: XK
authors.lastname: Tong
authors.forename: Nektaria
authors.initials: N
authors.lastname: Nicolakakis
authors.forename: Ara
authors.initials: A
authors.lastname: Kocharyan
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D017772:Amyloid Neuropathies / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000098:blood supply*; D001927:Brain Diseases / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D002540:Cerebral Cortex / Q000098:blood supply; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000494:pharmacology; D015291:Transforming Growth Factors / Q000235:genetics / Q000378:metabolism*; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015291:Transforming Growth Factors; D002374:Catalase; D013482:Superoxide Dismutase