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

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