Effect of Melatonin on Lipid Membrane Structure and Membrane Interactions with Amyloid. An NMR and LSPR Study

Abstract

Alzheimer's Disease (AD) is a neurodegenerative disease and leading cause of dementia resulting in memory loss and cognition decline. The molecular mechanism of AD is not well understood, which has delayed the development of effective treatments. Amyloid-ß (Aß) is the suspected cause of AD, as nonspecific interactions of toxic amyloid oligomers with the plasma membrane cause neuronal cell death. Melatonin is a hormone produced by pineal gland to regulate sleep cycle and has been shown to be protective against Aß in cellular and animal studies, but the molecular mechanism is not well understood. Melatonin can partition into lipid membranes and has remarkable effects on their biophysical properties; this may be important in explaining its protective effects. In this study, we aimed to determine the effect of melatonin on the phase behaviour of model lipid membranes and its ability to inhibit amyloid interaction with lipid bilayers, using nuclear magnetic resonance (NMR) and localized surface plasmon resonance (LSPR), respectively. We used a tertiary mixture of DPPC, POPC, and cholesterol bilayers as a lipid model. Fully hydrated multilamellar lipid stacks were used in solid-state ²H-NMR experiments, showing that melatonin competes with cholesterol to associate with certain lipids and promotes the coexistence of liquid ordered and liquid disordered phases in a temperature-dependent manner. We studied membrane interactions with Aß (1-42) using LSPR and determined that the incorporation of melatonin into the lipid bilayer leads to a decrease in the nonspecific binding of Aß to the supported lipid bilayer. Combining the results from both techniques, we conclude that melatonin's protective effect against amyloid toxicity in lipid membranes is due to its ability to change the structural properties of the membrane and to reduce amyloid affinity to such membranes.