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

INTRODUCTION

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.

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 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.

DISCUSSION

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.

HIGHLIGHTS

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.