Premium
Removal of membrane cholesterol selectively restores K IR channel function in brain endothelium during Alzheimer's disease
Author(s) -
Hakim Md. Abdul,
Behringer Erik
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02103
Subject(s) - endothelium , chemistry , biophysics , blood–brain barrier , cholesterol , medicine , endocrinology , endothelial dysfunction , membrane potential , hyperpolarization (physics) , biochemistry , biology , central nervous system , organic chemistry , nuclear magnetic resonance spectroscopy
The number of Alzheimer's disease (AD) patients (~44 million worldwide; ~5.8 million Americans) continues to rise, while there is no effective treatment available and etiology remains obscure. Incidence of AD increases with aging due, in large part, to deteriorating endothelial control of blood flow throughout the brain. Further, K + channels, particularly inward‐rectifying K + (K IR 2.x) channels, are integral to endothelial function and optimal perfusion of brain parenchyma. Our group has identified reduced K IR 2.x channel function as a new manifestation of endothelial “dysfunction” during aging and AD, whereas function of small‐ and intermediate‐Ca 2+ ‐activated K + (SK Ca /IK Ca ) channels is stable throughout. Moreover, we reasoned that apparently deficient K IR 2.x channels could be due to their aberrant interaction with plasma membrane cholesterol, a major regulator of membrane fluidity and ion channels. Hence, we tested the hypothesis that reduction of membrane cholesterol may restore K IR channel function in brain endothelium of old AD mice . Membrane potential (V m ) was measured in posterior cerebral endothelial “tubes” of female 3xTg‐AD mice (16 to 19 mo; n=12) before and after mild treatment with the cholesterol‐removing agent methyl‐β‐cyclodextrin (MβCD; 1 mM). We used elevated extracellular potassium([K + ] E ;15 mM) and NS309 (1 µM) to activate K IR 2.x and SK Ca /IK Ca channels respectively. SK Ca /IK Ca channel function for producing hyperpolarization (more negative V m ) remains stable after MβCD treatment (ΔV m , mV; ‐31±1 vs. control, ‐33±2), revealing that SK Ca /IK Ca channels are not significantly impacted by membrane cholesterol. However, K IR 2.x channel function is progressively restored and enhanced in a time‐dependent manner following washout of MβCD (ΔV m , mV; control, ‐5±1; 30 min washout, ‐9±1; 60 min, ‐14±1). Altogether, our findings demonstrate that cholesterol intervention of brain endothelium selectively restores K IR 2.x vs. SK Ca /IK Ca channel function during AD. Thus, endothelial cholesterol‐K IR channel interaction is a novel therapeutic target for ameliorating cerebrovascular function to optimize perfusion of the AD brain.