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阿尔茨海默病小鼠模型中脑微血管BK功能障碍的性别特异性机制

Sex-specific mechanisms of cerebral microvascular BK dysfunction in a mouse model of Alzheimer's disease.

作者信息

Silva Josiane F, Polk Felipe D, Martin Paige E, Thai Stephenie H, Savu Andrea, Gonzales Matthew, Kath Allison M, Gee Michael T, Pires Paulo W

机构信息

Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, USA.

Sarver Heart Center, University of Arizona College of Medicine, Tucson, Arizona, USA.

出版信息

Alzheimers Dement. 2025 Feb;21(2):e14438. doi: 10.1002/alz.14438. Epub 2024 Dec 19.

DOI:10.1002/alz.14438
PMID:39698895
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11848394/
Abstract

INTRODUCTION

Cerebrovascular dysfunction occurs in Alzheimer's disease (AD), impairing hemodynamic regulation. Large conductance Ca-activated K channels (BK) regulate cerebrovascular reactivity and are impaired in AD. BK activity depends on intracellular Ca (Ca sparks) and nitro-oxidative post-translational modifications. However, whether these mechanisms underlie BK impairment in AD remains unknown.

METHODS

Cerebral arteries from 5x-FAD and wild-type (WT) littermates were used for molecular biology, electrophysiology, ex vivo, and in vivo experiments.

RESULTS

Arterial BK activity is reduced in 5x-FAD via sex-dependent mechanisms: in males, there is lower BK subunit expression and less Ca sparks. In females, we observed reversible nitro-oxidative modification of BK. Further, BK is involved in hemodynamic regulation in WT mice, and its dysfunction is associated with vascular deficits in 5x-FAD.

DISCUSSION

Our data highlight the central role played by BK in cerebral hemodynamic regulation and that molecular mechanisms of its impairment diverge based on sex in 5x-FAD.

HIGHLIGHTS

Cerebral microvascular BK dysfunction occurs in both female and male 5x-FAD. Reduction in BK subunit protein and Ca sparks drive the dysfunction in males. Nitro-oxidative stress is present in females, but not males, 5x-FAD. Reversible nitro-oxidation of BK underlies BK dysfunction in female 5x-FAD.

摘要

引言

阿尔茨海默病（AD）中会出现脑血管功能障碍，损害血流动力学调节。大电导钙激活钾通道（BK）调节脑血管反应性，且在AD中受损。BK活性依赖于细胞内钙（钙火花）和硝基氧化翻译后修饰。然而，这些机制是否是AD中BK受损的基础仍不清楚。

方法

使用来自5x-FAD和野生型（WT）同窝小鼠的脑动脉进行分子生物学、电生理学、体外和体内实验。

结果

5x-FAD中动脉BK活性通过性别依赖机制降低：在雄性中，BK亚基表达较低且钙火花较少。在雌性中，我们观察到BK的可逆硝基氧化修饰。此外，BK参与WT小鼠的血流动力学调节，其功能障碍与5x-FAD中的血管缺陷有关。

讨论

我们的数据突出了BK在脑血流动力学调节中的核心作用，以及在5x-FAD中其受损的分子机制因性别而异。

要点

雌性和雄性5x-FAD中均出现脑微血管BK功能障碍。BK亚基蛋白和钙火花的减少导致雄性功能障碍。5x-FAD雌性中存在硝基氧化应激，而雄性中不存在。BK的可逆硝基氧化是雌性5x-FAD中BK功能障碍的基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/43306ca98b7a/ALZ-21-e14438-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/d3160cbbc26d/ALZ-21-e14438-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/eac69883e52b/ALZ-21-e14438-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/ac93689948a2/ALZ-21-e14438-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/d03bf72c2775/ALZ-21-e14438-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/1daf7b4ee0e2/ALZ-21-e14438-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/32973b0ed983/ALZ-21-e14438-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/a3c8e550169e/ALZ-21-e14438-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/43306ca98b7a/ALZ-21-e14438-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/d3160cbbc26d/ALZ-21-e14438-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/eac69883e52b/ALZ-21-e14438-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/ac93689948a2/ALZ-21-e14438-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/d03bf72c2775/ALZ-21-e14438-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/1daf7b4ee0e2/ALZ-21-e14438-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/32973b0ed983/ALZ-21-e14438-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/a3c8e550169e/ALZ-21-e14438-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7374/11848394/43306ca98b7a/ALZ-21-e14438-g002.jpg

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本文引用的文献

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Estradiol improves behavior in FAD transgenic mice that express but not after ovariectomy.雌二醇可改善表达但不表达 的 FAD 转基因小鼠的行为，这些小鼠在去卵巢后。
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Uncoupling of Ca sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia.
高血压诱导血管性痴呆中脑动脉的钙火花与 BK 通道解偶联导致低灌注。
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