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

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's & Dementia Pub Date : 2024-12-19 DOI:10.1002/alz.14438

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

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Abstract

INTRODUCTION

Cerebrovascular dysfunction occurs in Alzheimer's disease (AD), impairing hemodynamic regulation. Large conductance Ca²⁺-activated K⁺ channels (BK_Ca) regulate cerebrovascular reactivity and are impaired in AD. BK_Ca activity depends on intracellular Ca²⁺ (Ca²⁺ sparks) and nitro-oxidative post-translational modifications. However, whether these mechanisms underlie BK_Ca 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_Ca activity is reduced in 5x-FAD via sex-dependent mechanisms: in males, there is lower BK_α subunit expression and less Ca²⁺ sparks. In females, we observed reversible nitro-oxidative modification of BK_Ca. Further, BK_Ca 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_Ca in cerebral hemodynamic regulation and that molecular mechanisms of its impairment diverge based on sex in 5x-FAD.

Highlights

Cerebral microvascular BK_Ca dysfunction occurs in both female and male 5x-FAD.
Reduction in BK_α 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 BK_α underlies BK_Ca dysfunction in female 5x-FAD.

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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

脑血管功能障碍发生在阿尔茨海默病（AD），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，并在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，这些机制是否构成AD患者BKCa损伤的基础尚不清楚。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.