BK channel dysfunction underlies small vessel disease of the brain in both hypertension and Alzheimer's disease

Abstract

Alzheimer's disease (AD) and hypertension-related vascular dementia share many common clinical and radiological features including cerebral small vessel disease (cSVD) of the brain, thought to be the mechanism behind the reduction in cerebral blood flow (CBF). The aim of this study was to determine if there are common mechanisms underlying a reduced CBF in dementia. CBF is determined by depolarisation induced contraction of arterial smooth muscle cells (SMCs). This contraction is buffered by the activation of the large-conductance Ca 2+ -activated K + (BK) channels on the plasma membrane (PM), by transient localised Ca 2+ release from ryanodine receptors (RyR) on the sarcoplasmic reticulum (SR), known as Ca 2+ sparks.Hypothesis: Defects in BK channel activation leads to the cSVD phenotype in these diseases.8-month old male spontaneously hypertensive (BPH/2) mice and normotensive controls (BPN/3) were used to study hypertension-induced cSVD. To study AD related cSVD we used 18–20 month old male APP23 mice. We used a range of physiological techniques to investigate vascular ion channel function within the cerebral microvasculature. Laser Doppler flowmetry and behavioural assessments were performed on the BPH/2 and BPN/3 mice to initially determine if they are a model of hypertension-related vascular dementia.BPH/2 mice displayed reduced CBF and cognitive impairment. Pressure-induced constriction from cerebral pial arteries was significantly greater in both the BPH/2 and APP23 animals compared to controls. This was the result of reduced BK channel activity, as confirmed by reduced constriction to the BK channel blocker paxilline. Electrophysiology experiments showed a decrease in spontaneous transient outward currents, which represent BK channel activation by Ca 2+ sparks. In the APP23 model, this attenuated BK channel activation was due to reduced Ca 2+ spark frequency. However, in the BPH/2 mice, Ca 2+ spark frequency was equal between hypertensive and normotensive mice. Furthermore, there were no differences in single channel BK channel activity over a range of [Ca 2+ ]. Live cell imaging of isolated SMCs labelled with membrane dyes, showed a reduced interaction between the SR and the PM. Proximity ligation assay was used on fixed SMCs to determine if BK channel and RyR are within 40 nm of each other. SMCs from BPH/2 cerebral arteries has significantly less puncta suggesting a physical separation between Ca 2+ sparks and BK channel, rendering the [Ca 2+ ] local to the BK channel insufficient for activation.Our data indicate that vascular BK channel dysfunction is a common mechanism underpinning reduced CBF in SVD. Therapies aimed at improving vascular BK channel function could provide new therapeutic targets for both AD and hypertension-induced vascular dementia. British Heart Foundation This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.