Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 48, Pages 11165-11174Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4031-05.2005
Keywords
amyloid-beta; transforming growth factor-beta 1; transgenic mouse models; cerebral blood vessels; superoxide dismutase; vascular endothelial growth factor
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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-beta 1 (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.
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