Melatonin Changes Domain Structure and Protects Model Neuronal Membranes Against Damage Caused by Amyloid-Beta

Abstract

The amyloid-β(1-42) peptide is a major player in Alzheimer's disease—a debilitating neurodegenerative disorder that causes memory loss and neuronal damage in elderly patients. Amyloid-β(1-42) forms toxic oligomers that bind to neuronal membranes through interactions with cholesterol-rich lipid rafts. These interactions result in damage to the lipid membrane through the insertion of the amyloid-β(1-42) peptide and subsequent formation of an ion channel or pore. Melatonin, a hormone naturally produced in the brain during sleep, has been identified as a potentially protective native molecule in cellular and animal studies however the molecular mechanisms of its protection are not well understood. Due to its lipophilicity, melatonin partitions into neural model membranes and associates with the lipid headgroups. In this study we used atomic force microscopy (AFM), and Kelvin probe force microscopy (KPFM) techniques to elucidate the effect of melatonin on the structure and domain organization in neuronal model membranes composed of DOPC, POPC, gangliosides, sphingomyelin, and cholesterol. In addition we measured membrane permeability using black lipid membrane (BLM) techniques on the same neuronal models to elucidate the protective effect of melatonin against the damage induced by amyloid-β peptide ion channels. We demonstrated that melatonin changes the structure of neuronal model membranes (both topographical and electrostatic changes in the nanoscale domains) and reduces the ion current (a measure of damage) across model membranes induced by the binding of the amyloid-β(1-42) peptide.