Amyloid-beta (Aβ) peptide accumulation on blood vessels in the brain is a hallmark of neurodegeneration. While Aβ peptides constrict cerebral arteries and arterioles, their impact on capillaries is less understood. Aβ was recently shown to constrict brain capillaries through pericyte contraction, but whether-and if so how-Aβ affects endothelial cells (ECs) remains unknown. ECs represent the predominant vascular cell type in the cerebral circulation, and we recently showed that the mechanosensitive ion channel Piezo1 is functionally expressed in the plasma membrane of ECs. Since Aβ disrupts membrane structures, we hypothesized that Aβ1-40, the predominantly deposited isoform in the cerebral circulation, alters endothelial Piezo1 function. Using patch clamp electrophysiology and freshly isolated capillary ECs, we assessed the impact of Aβ1-40 peptide on single-channel Piezo1 activity. We show that Aβ1-40 increased Piezo1 open probability and the channel open time. Aβ1-40 effects were absent when Piezo1 was genetically deleted or when a superoxide dismutase/catalase mimetic was used. Further, Aβ1-40 enhanced Piezo1 mechanosensitivity and lowered the pressure of half-maximal Piezo1 activation. Our data collectively suggest that Aβ1-40 facilitates higher Piezo1-mediated cation influx in brain ECs. These novel findings have the potential to unravel the possible involvement of Piezo1 modulation in the pathophysiology of neurodegenerative diseases characterized by Aβ accumulation.

中文翻译：

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淀粉样蛋白 β Aβ1-40 激活脑毛细血管内皮细胞中的 Piezo1 通道。


淀粉样蛋白-β （Aβ） 肽在大脑血管上的积累是神经退行性疾病的标志。虽然 Aβ 肽会收缩脑动脉和小动脉，但它们对毛细血管的影响尚不清楚。最近显示 Aβ 通过周细胞收缩收缩脑毛细血管，但 Aβ 是否以及如何影响内皮细胞 （EC） 仍然未知。ECs 代表脑循环中的主要血管细胞类型，我们最近表明机械敏感离子通道 Piezo1 在 ECs 的质膜中功能上表达。由于 Aβ 破坏膜结构，我们假设 Aβ1-40（脑循环中主要沉积的亚型）改变了内皮压电 1 功能。使用膜片钳电生理学和新鲜分离的毛细管 EC，我们评估了 Aβ1-40 肽对单通道 Piezo1 活性的影响。我们表明 Aβ1-40 增加了 Piezo1 打开概率和通道打开时间。当 Piezo1 被基因删除或使用超氧化物歧化酶/过氧化氢酶模拟物时，不存在 Aβ1-40 效应。此外，Aβ1-40 增强了 Piezo1 的机械敏感性并降低了半最大 Piezo1 激活的压力。我们的数据共同表明，Aβ1-40 促进了脑 ECs 中更高的 Piezo1 介导的阳离子流入。这些新发现有可能揭示 Piezo1 调节可能参与以 Aβ 积累为特征的神经退行性疾病的病理生理学。