The accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary calcium (Ca2+) signals to direct blood flow. The initiation and amplification of endothelial cell Ca2+ signals require an intact microtubule cytoskeleton. Since tau accumulation in endothelial cells disrupts native microtubule stability, we reasoned that tau-induced microtubule destabilization would impair endothelial Ca2+ signaling. We tested the hypothesis that tau disrupts the regulation of local cerebral blood flow by reducing endothelial cell Ca2+ signals and endothelial-dependent vasodilation. We used a pathogenic soluble tau peptide (T-peptide) model of tau aggregation and mice with genetically encoded endothelial Ca2+ sensors to measure cerebrovascular endothelial responses to tau exposure. T-peptide significantly attenuated endothelial Ca2+ activity and cortical capillary blood flow in vivo. Further, T-peptide application constricted pressurized cerebral arteries and inhibited endothelium-dependent vasodilation. This study demonstrates that pathogenic tau alters cerebrovascular function through direct attenuation of endothelial Ca2+ signaling and endothelium-dependent vasodilation.

中文翻译：

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致病性可溶性 tau 肽破坏脑微血管中的内皮钙信号传导和血管舒张

微管相关 tau 蛋白在血管内和周围的积累会通过尚未完全了解的机制导致脑微血管功能障碍。营养物质输送到大脑中活跃的神经元依赖于毛细血管钙（Ca2+）信号引导血流。内皮细胞Ca的启动和扩增2+信号需要完整的微管细胞骨架。由于 tau 在内皮细胞中的积累会破坏天然微管的稳定性，因此我们推断 tau 诱导的微管不稳定会损害内皮细胞 Ca2+发信号。我们测试了以下假设：tau 通过减少内皮细胞 Ca2+ 来破坏局部脑血流的调节2+信号和内皮依赖性血管舒张。我们使用了 tau 聚集的致病性可溶性 tau 肽（T 肽）模型和具有基因编码内皮 Ca 的小鼠2+传感器测量脑血管内皮细胞对 tau 暴露的反应。T 肽显着减弱内皮 Ca2+体内活动和皮质毛细血管血流量。此外，T 肽的应用可收缩受压的脑动脉并抑制内皮依赖性血管舒张。这项研究表明，致病性 tau 蛋白通过直接减弱内皮 Ca 来改变脑血管功能。2+信号传导和内皮依赖性血管舒张。