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The Journal of Neuroscience, November 30, 2005, 25(48):11165-11174; doi:10.1523/JNEUROSCI.4031-05.2005

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Neurobiology of Disease
Vascular Remodeling versus Amyloid -Induced Oxidative Stress in the Cerebrovascular Dysfunctions Associated with Alzheimer's Disease

Xin-Kang Tong, Nektaria Nicolakakis, Ara Kocharyan, and Edith Hamel

Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada H3A 2B4

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-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.

Key words: amyloid-; transforming growth factor-1; transgenic mouse models; cerebral blood vessels; superoxide dismutase; vascular endothelial growth factor

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Received June 3, 2005; accepted October 15, 2005.

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