Vascular remodeling versus amyloid beta-induced oxidative stress in the cerebrovascular dysfunctions associated with Alzheimer's disease.
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.
Tong
Xin-Kang
XK
Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, H3A 2B4, Canada.
Nicolakakis
Nektaria
N
Kocharyan
Ara
A
Hamel
Edith
E
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
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015291:Transforming Growth Factors; D002374:Catalase; D013482:Superoxide Dismutase