Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes
Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes
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DOI：
10.1126/science.aav9518
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发表时间：
2019-07-19
期刊：
影响因子：
56.9
通讯作者：
Attwell, David
中科院分区：
文献类型：
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作者：
Nortley, Ross;Korte, Nils;Attwell, David
在阿尔茨海默病(AD)发病的早期，脑血流就会减少。因为大脑内的大部分血管阻力都在毛细血管中，这可能反映了毛细血管壁上收缩周细胞的功能障碍。我们使用活体和快速固定的人体组织来确定疾病的相关性，并通过啮齿动物实验来确定机制。我们发现，在认知功能减退的人类中，淀粉样β蛋白(Aβ)会收缩周细胞位置的大脑毛细血管。这是由Aβ产生的活性氧引起的，它引起内皮素-1(ET)的释放，激活周细胞ETA受体。在阿尔茨海默病的小鼠模型中，毛细血管而不是微动脉也发生了收缩。因此，抑制Aβ引起的毛细血管收缩可能会减少AD患者的能量缺乏和神经变性。
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 beta (A beta) constricts brain capillaries at pericyte locations. This was caused by A beta 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 A beta could potentially reduce energy lack and neurodegeneration in AD.