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+ (KIR) channel function in animal models of aging and AD compromises endothelial function and optimal perfusion of brain parenchyma. Deficient endothelial KIR 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 KIR 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 KIR and Ca2+-activated K+ (SKCa/IKCa) channels respectively before and after MβCD treatment. Results: SKCa/IKCa channel function for producing hyperpolarization remained stable regardless of age group and MβCD treatment (ΔVm: ∼–33 mV). However, as deficient during AD, KIR channel function was restored (ΔVm: –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 KIR versus SKCa/IKCa channel function during AD. Thus, the endothelial cholesterol-KIR channel interface is a novel target for ameliorating perfusion of the AD brain.
Stabilizing ER Ca2+ Channel Function as an Early Preventative Strategy for Alzheimer’s Disease
