Vascular remodeling versus amyloid beta-induced oxidative stress in the cerebrovascular dysfunctions associated with Alzheimer's disease

• Published in: The Journal of neuroscience 2005-11, Vol.25 (48), p.11165-11174
• Main Authors: Tong, Xin-Kang, Nicolakakis, Nektaria, Kocharyan, Ara, Hamel, Edith
• Format: Article
• Language: English
• Subjects: Aged; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Neuropathies - metabolism; Animals; Blood Vessels - metabolism; Blood Vessels - physiopathology; Brain - blood supply; Brain Diseases - metabolism; Catalase - pharmacology; Cerebral Cortex - blood supply; Female; Humans; Male; Mice; Mice, Transgenic; Microcirculation; Neurobiology of Disease; Oxidative Stress; Superoxide Dismutase - pharmacology; Transforming Growth Factors - genetics; Transforming Growth Factors - metabolism; Vasomotor System - drug effects; Vasomotor System - physiopathology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.4031-05.2005

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.