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

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.