Sex-specific mechanisms of cerebral microvascular BKCadysfunction in a mouse model of Alzheimer’s disease

Background Cerebral microvascular dysfunction and nitro-oxidative stress are present in patients with Alzheimer’s disease (AD) and may contribute to disease progression and severity. Large conductance Ca 2+ -activated K + channels (BK Ca ) play an essential role in vasodilatory responses and maintenance of myogenic tone in resistance arteries. BK Ca impairment can lead to microvascular dysfunction and hemodynamic deficits in the brain. We hypothesized that reduced BK Ca function in cerebral arteries mediates microvascular and neurovascular responses in the 5x-FAD model of AD. Methods BK Ca activity in the cerebral microcirculation was assessed by patch clamp electrophysiology and pressure myography, in situ Ca 2+ sparks by spinning disk confocal microscopy, hemodynamics by laser speckle contrast imaging. Molecular and biochemical analyses were conducted by affinity-purification assays, qPCR, Western blots and immunofluorescence. Results We observed that pial arteries from 5-6 months-old male and female 5x-FAD mice exhibited a hyper-contractile phenotype than wild-type (WT) littermates, which was linked to lower vascular BK Ca activity and reduced open probability. In males, BK Ca dysfunction is likely a consequence of an observed lower expression of the pore-forming subunit BK α and blunted frequency of Ca 2+ sparks, which are required for BK Ca activity. However, in females, impaired BK Ca function is, in part, a consequence of reversible nitro-oxidative changes in the BK α subunit, which reduces its open probability and regulation of vascular tone. We further show that BK Ca function is involved in neurovascular coupling in mice, and its dysfunction is linked to neurovascular dysfunction in the model. Conclusion These data highlight the central role played by BK Ca in cerebral microvascular and neurovascular regulation, as well as sex-dependent mechanisms underlying its dysfunction in a mouse model of AD.