TY - JOUR
T1 - Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-β
AU - Park, Laibaik
AU - Wang, Gang
AU - Zhou, Ping
AU - Zhou, Joan
AU - Pitstick, Rose
AU - Previti, Mary Lou
AU - Younkin, Linda
AU - Younkin, Steven G.
AU - Van Nostrand, William E.
AU - Cho, Sunghee
AU - Anrather, Josef
AU - Carlson, George A.
AU - Iadecola, Costantino
PY - 2011/3/22
Y1 - 2011/3/22
N2 - Increasing evidence indicates that cerebrovascular dysfunction plays a pathogenic role in Alzheimer's dementia (AD). Amyloid-β (Aβ), 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 Aβ to NADPH oxidase-dependent vascular oxidative stress have not been identified, however. We report that the scavenger receptor CD36, a membrane glycoprotein that binds Aβ, is essential for the vascular oxidative stress and neurovascular dysfunction induced by Aβ1-40. Thus, topical application of Aβ1-40 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 (CD360/0). The cerebrovascular effects of infusion of Aβ1-40 into cerebral arteries are not observed in mice pretreated with CD36 blocking antibodies or in CD360/0 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 Aβ1-40. CD36 is also required for the vascular oxidative stress induced by exogenous Aβ1-40 or observed in Tg2576 mice. These observations establish CD36 as a key link between Aβ1-40 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 Aβ.
AB - Increasing evidence indicates that cerebrovascular dysfunction plays a pathogenic role in Alzheimer's dementia (AD). Amyloid-β (Aβ), 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 Aβ to NADPH oxidase-dependent vascular oxidative stress have not been identified, however. We report that the scavenger receptor CD36, a membrane glycoprotein that binds Aβ, is essential for the vascular oxidative stress and neurovascular dysfunction induced by Aβ1-40. Thus, topical application of Aβ1-40 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 (CD360/0). The cerebrovascular effects of infusion of Aβ1-40 into cerebral arteries are not observed in mice pretreated with CD36 blocking antibodies or in CD360/0 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 Aβ1-40. CD36 is also required for the vascular oxidative stress induced by exogenous Aβ1-40 or observed in Tg2576 mice. These observations establish CD36 as a key link between Aβ1-40 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 Aβ.
KW - Alzheimer's disease
KW - Functional hyperemia
KW - Nox2
KW - Receptor for advanced glycation end-products
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U2 - 10.1073/pnas.1015413108
DO - 10.1073/pnas.1015413108
M3 - Article
C2 - 21383152
AN - SCOPUS:79953213351
SN - 0027-8424
VL - 108
SP - 5063
EP - 5068
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -