Brain capillary Piezo1 ion channels and blood flow regulation in Alzheimer’s Disease

摘要： 阿尔茨海默病患者脑毛细血管Piezo1离子通道与血流调节 脑毛细血管是大脑中最小的血管，对感知脑血管的代谢需求至关重要。 激活神经元，并通过供应更多的血液来回应这些需求。值得注意的是，这一功能在 神经退行性疾病，如阿尔茨海默病。不仅是毛细血管的感觉在 阿尔茨海默病，血管僵硬和毛细血管血流完全中断，称为毛细血管 失速，已经在阿尔茨海默病的小鼠模型中观察到。鉴于毛细管的失速破坏了 毛细血管所受的血流动力，了解阿尔茨海默病 与改变的机械感应能力有关。我们最近发现Piezo1蛋白是一种 大脑毛细血管中的机械传感器。在这里，我们测试了改变的Piezo1通道活动是 与阿尔茨海默病的脑血流量减少有关。我们进一步推测调谐Piezo1 活动会改善脑血流。我们将研究内皮Piezo1通道对 阿尔茨海默病小鼠模型中的毛细血管停滞和血流减少。使用毛细血管内皮细胞 野生型和阿尔茨海默病小鼠的细胞，我们将使用创新的电生理和分子 阿尔茨海默病期间Piezo1离子通道表达和功能是否改变的评估方法 疾病。在第二个目标中，我们将利用体内高分辨率的双光子显微镜来研究毛细血管。 阿尔茨海默病小鼠在药物操纵Piezo1时的失速和血流变化 频道。这项新颖的工作可能会带来以前没有测试过的新的治疗策略。

Summary: Brain capillary Piezo1 ion channels and blood flow regulation in Alzheimer’s Disease Brain capillaries are the smallest blood vessels in the brain and are crucial in sensing the metabolic needs of active neurons and responding to these needs by supplying more blood. Notably, this function is impaired during neurodegenerative diseases such as Alzheimer’s disease. Not only that capillary sensing is impaired during Alzheimer’s disease, vascular stiffness and complete disruption of capillary blood flow, referred to as capillary stalling, have been observed in mouse models of Alzheimer’s disease. Given that capillary stalling disrupts the hemodynamic forces that capillaries are exposed to, it is important to understand whether Alzheimer’s disease associates with altered mechano-sensing abilities. We recently discovered that the protein Piezo1 is a mechanosensor in brain capillaries. Here, we test the overall hypothesis that altered Piezo1 channel activity is involved in the reduction of brain blood flow in Alzheimer’s disease. We further speculate that tuning Piezo1 activity will improve cerebral blood flow. We will investigate the contribution of endothelial Piezo1 channels to capillary stalling and blood flow reductions in a mouse model of Alzheimer’s disease. Using capillary endothelial cells from wild-type and Alzheimer’s disease mice, we will employ innovative electrophysiological and molecular approaches to assess whether Piezo1 ion channel expression and function are altered during Alzheimer’s disease. In the second aim, we will utilize in vivo high-resolution, two-photon microscopy to investigate capillary stalling and blood flow changes in Alzheimer’s disease mice while pharmacologically manipulating Piezo1 channels. This novel work could lead to new therapeutic strategies not previously tested.