Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 12, Pages 5063-5068Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1015413108
Keywords
Alzheimer's disease; functional hyperemia; Nox2; receptor for advanced glycation end-products
Categories
Funding
- National Institutes of Health [NS37853, NS55118, NS41997]
- American Heart Association [09SDG2060701]
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Increasing evidence indicates that cerebrovascular dysfunction plays a pathogenic role in Alzheimer's dementia (AD). Amyloid-beta (A beta), a peptide central to the pathogenesis of AD, has profound vascular effects mediated, for the most part, by reactive oxygen species produced by the enzyme NADPH oxidase. The mechanisms linking A beta to NADPH oxidase-dependent vascular oxidative stress have not been identified, however. We report that the scavenger receptor CD36, a membrane glycoprotein that binds A beta, is essential for the vascular oxidative stress and neurovascular dysfunction induced by A beta(1-40). Thus, topical application of A beta(1-40) onto the somatosensory cortex attenuates the increase in cerebral blood flow elicited by neural activity or by endothelium-dependent vasodilators in WT mice but not in CD36-null mice (CD36(0/0)). The cerebrovascular effects of infusion of A beta(1-40) into cerebral arteries are not observed in mice pretreated with CD36 blocking antibodies or in CD36(0/0) mice. Furthermore, CD36 deficiency prevents the neurovascular dysfunction observed in transgenic mice overexpressing the Swedish mutation of the amyloid precursor protein Tg2576 despite elevated levels of brain A beta(1-40). CD36 is also required for the vascular oxidative stress induced by exogenous A beta(1-40) or observed in Tg2576 mice. These observations establish CD36 as a key link between A beta(1-40) and the NADPH oxidase-dependent vascular oxidative stress underlying the neurovascular dysfunction and suggest that CD36 is a potential therapeutical target to counteract the cerebrovascular dysfunction associated with A beta.
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