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 |
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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. |
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ISSN: | 1552-5260 1552-5279 |
DOI: | 10.1002/alz.14438 |