Midazolam inhibits the formation of amyloid fibrils and GM1 ganglioside-rich microdomains in presynaptic membranes through the gamma-aminobutyric acid A receptor

Recent studies have suggested that a positive correlation exists between surgical interventions performed under general anesthesia and the risk of developing Alzheimer's disease (AD) in the late postoperative period. It has been reported that amyloid beta-protein (A beta) fibrillogenesis, which is closely related to AD, is accelerated by exposure to anesthetics. However, the mechanisms underlying these effects remain uncertain. This study was designed to investigate whether the anesthetic midazolam affects A beta fibrillogenesis, and if so, whether it acts through GM! ganglioside (GM1) on the neuronal surface. Midazolam treatment decreased GM1 expression in the detergent-resistant membrane microdomains of neurons, and these effects were regulated by the gamma-aminobutyric acid-A receptor. Midazolam inhibited A beta fibril formation from soluble A beta on the neuronal surface. In addition, midazolam suppressed GM1-induced fibril formation in a cell-free system. Moreover, midazolam inhibited the formation of All assemblies in synaptosomes isolated from aged mouse brains. These finding suggested that midazolam has direct and indirect inhibitory effects on A beta fibrillogenesis. (C) 2015 Elsevier Inc. All rights reserved.