Methyl-Beta-Cyclodextrin Restores K_IR Channel Function in Brain Endothelium of Female Alzheimer's Disease Mice

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.

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.

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 Ca²⁺-activated K⁺ (SK_Ca/IK_Ca) channels respectively before and after MβCD treatment.

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.

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.