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

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-translation...

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Veröffentlicht in:Alzheimer's & dementia 2024-12
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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. Cerebral arteries from 5x-FAD and wild-type (WT) littermates were used for molecular biology, electrophysiology, ex vivo, and in vivo experiments. 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. 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. 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.
ISSN:1552-5260
1552-5279
DOI:10.1002/alz.14438