INTRODUCTIONCerebrovascular dysfunction occurs in Alzheimer's disease (AD), impairing hemodynamic regulation. Large conductance Ca2+‐activated K+ channels (BKCa) regulate cerebrovascular reactivity and are impaired in AD. BKCa activity depends on intracellular Ca2+ (Ca2+ sparks) and nitro‐oxidative post‐translational modifications. However, whether these mechanisms underlie BKCa impairment in AD remains unknown.METHODSCerebral arteries from 5x‐FAD and wild‐type (WT) littermates were used for molecular biology, electrophysiology, ex vivo, and in vivo experiments.RESULTSArterial BKCa activity is reduced in 5x‐FAD via sex‐dependent mechanisms: in males, there is lower BKα subunit expression and less Ca2+ sparks. In females, we observed reversible nitro‐oxidative modification of BKCa. Further, BKCa is involved in hemodynamic regulation in WT mice, and its dysfunction is associated with vascular deficits in 5x‐FAD.DISCUSSIONOur data highlight the central role played by BKCa in cerebral hemodynamic regulation and that molecular mechanisms of its impairment diverge based on sex in 5x‐FAD.Highlights Cerebral microvascular BKCa dysfunction occurs in both female and male 5x‐FAD. Reduction in BKα subunit protein and Ca2+ sparks drive the dysfunction in males. Nitro‐oxidative stress is present in females, but not males, 5x‐FAD. Reversible nitro‐oxidation of BKα underlies BKCa dysfunction in female 5x‐FAD.

中文翻译：

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阿尔茨海默病小鼠模型中脑微血管 BKCa 功能障碍的性别特异性机制


引言阿尔茨海默病 （AD） 中发生肾血管功能障碍，损害血流动力学调节。大电导 Ca2+ 激活的 K+ 通道 （BKCa） 调节脑血管反应性，在 AD 中受损。BKCa 活性取决于细胞内 Ca2+（Ca2+ 火花）和硝基氧化翻译后修饰。然而，这些机制是否是 AD 中 BKCa 损伤的基础仍然未知。方法来自 5x-FAD 和野生型 （WT） 同窝体的动脉用于分子生物学、电生理学、离体和体内实验。结果通过性别依赖性机制，在 5x-FAD 中，BDCa 活性降低：在男性中，BKα 亚基表达较低，Ca2+ 火花较少。在雌性中，我们观察到 BKCa 的可逆硝基氧化修饰。此外，BKCa 参与 WT 小鼠的血流动力学调节，其功能障碍与 5x-FAD 中的血管缺损有关。讨论我们的数据强调了 BKCa 在脑血流动力学调节中发挥的核心作用，并且其损伤的分子机制在 5x-FAD 中根据性别而有所不同。亮点 脑微血管 BKCa 功能障碍发生在女性和男性 5x-FAD 中。BKα 亚基蛋白和 Ca2+ 火花的减少导致男性功能障碍。硝基氧化应激存在于女性中，但男性不存在，即 5x-FAD。BKα 的可逆硝基氧化是女性 5x-FAD 中 BKCa 功能障碍的基础。