| First Author | Hakim MA | Year | 2021 |
| Journal | J Alzheimers Dis Rep | Volume | 5 |
| Issue | 1 | Pages | 693-703 |
| PubMed ID | 34755043 | Mgi Jnum | J:358647 |
| Mgi Id | MGI:7782792 | Doi | 10.3233/ADR-210016 |
| Citation | Hakim MA, et al. (2021) Methyl-Beta-Cyclodextrin Restores K(IR) Channel Function in Brain Endothelium of Female Alzheimer's Disease Mice. J Alzheimers Dis Rep 5(1):693-703 |
| abstractText | 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-beta-cyclodextrin (MbetaCD) 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 MbetaCD (1 mmol/L). Elevated extracellular potassium ([K(+)](E); 15 mmol/L) and NS309 (1mumol/L) activated K(IR) and Ca(2+)-activated K(+) (SK(Ca)/IK(Ca)) channels respectively before and after MbetaCD treatment. RESULTS: SK(Ca)/IK(Ca) channel function for producing hyperpolarization remained stable regardless of age group and MbetaCD treatment (DeltaV(m): approximately -33 mV). However, as deficient during AD, K(IR) channel function was restored (DeltaV(m): -9+/-1 mV) versus pre-MbetaCD conditions (-5+/-1 mV); a progressive effect that reached -14+/-1 mV hyperpolarization at 60 min following MbetaCD washout. CONCLUSION: In female animals, MbetaCD 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. |
