Nortley, R;
Korte, N;
Izquierdo, P;
Hirunpattarasilp, C;
Mishra, A;
Jaunmuktane, Z;
Kyrargyri, V;
... Attwell, D; + view all
(2019)
Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes.
Science
, 365
(6450)
, Article 250. 10.1126/science.aav9518.
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Abstract
Cerebral blood flow is reduced early in Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. Here we used live and rapidly-fixed biopsied human tissue to establish disease-relevance, and rodent experiments to define mechanism. We found that, in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD.
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