Methyl-Beta-Cyclodextrin Restores K(IR) Channel Function in Brain Endothelium of Female Alzheimer’s Disease Mice

BACKGROUND: As the sixth-leading cause of death in the United States, Alzheimer’s disease (AD) entails deteriorating endothelial control of blood flow throughout the brain. In particular, reduced inward-rectifying K(+) (K(IR)) channel function in animal models of aging and AD compromises endothelial function and optimal perfusion of brain parenchyma. Deficient endothelial K(IR) channels may result from aberrant interaction with plasma membrane cholesterol as a primary regulator of membrane fluidity and ion channels. OBJECTIVE: We tested the hypothesis that mild methyl-β-cyclodextrin (MβCD) treatment to reduce membrane cholesterol may restore endothelial K(IR) channel function in brain endothelium of old AD mice. METHODS: Membrane potential was continuously measured in isolated endothelial tubes from posterior cerebral arteries of young (1 to 3 months) and old (16 to 19 months) female 3xTg-AD mice before and after mild treatment with the cholesterol-removing agent MβCD (1 mmol/L). Elevated extracellular potassium ([K(+)](E); 15 mmol/L) and NS309 (1μmol/L) activated K(IR) and Ca(2+)-activated K(+) (SK(Ca)/IK(Ca)) channels respectively before and after MβCD treatment. RESULTS: SK(Ca)/IK(Ca) channel function for producing hyperpolarization remained stable regardless of age group and MβCD treatment (ΔV(m): ∼–33 mV). However, as deficient during AD, K(IR) channel function was restored (ΔV(m): –9±1 mV) versus pre-MβCD conditions (–5±1 mV); a progressive effect that reached –14±1 mV hyperpolarization at 60 min following MβCD washout. CONCLUSION: In female animals, MβCD treatment of brain endothelium selectively restores K(IR) versus SK(Ca)/IK(Ca) channel function during AD. Thus, the endothelial cholesterol-K(IR) channel interface is a novel target for ameliorating perfusion of the AD brain.