TY - JOUR
T1 - Amyloid b oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes
AU - Nortley, Ross
AU - Korte, Nils
AU - Izquierdo, Pablo
AU - Hirunpattarasilp, Chanawee
AU - Mishra, Anusha
AU - Jaunmuktane, Zane
AU - Kyrargyri, Vasiliki
AU - Pfeiffer, Thomas
AU - Khennouf, Lila
AU - Madry, Christian
AU - Gong, Hui
AU - Richard-Loendt, Angela
AU - Huang, Wenhui
AU - Saito, Takashi
AU - Saido, Takaomi C.
AU - Brandner, Sebastian
AU - Sethi, Huma
AU - Attwell, David
N1 - Publisher Copyright:
© 2019 American Association for the Advancement of Science. All rights reserved.
PY - 2019/7/19
Y1 - 2019/7/19
N2 - Cerebral blood flow is reduced early in the onset of 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. 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 b (Ab) constricts brain capillaries at pericyte locations. This was caused by Ab 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 Ab could potentially reduce energy lack and neurodegeneration in AD.
AB - Cerebral blood flow is reduced early in the onset of 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. 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 b (Ab) constricts brain capillaries at pericyte locations. This was caused by Ab 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 Ab could potentially reduce energy lack and neurodegeneration in AD.
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U2 - 10.1126/science.aav9518
DO - 10.1126/science.aav9518
M3 - Article
C2 - 31221773
AN - SCOPUS:85068955336
SN - 0036-8075
VL - 365
JO - Science
JF - Science
IS - 6450
M1 - eaav9518
ER -