Axonal plasma membrane-mediated toxicity of cholesterol in Alzheimer's disease: A microsecond molecular dynamics study

Abstract

Alzheimer's disease is increasingly being recognized as an immune-mediated disease of brain. Since physiological brain health and brain immune function is dependent upon homeostatic neuronal membrane structure and function, alterations in membrane lipid biochemistry may predispose to disease. Brain is rich in cholesterol, and cholesterol metabolism dysfunction is a known risk factor for AD. Employing extensive microsecond all-atom molecular dynamics simulations, we investigated the properties of model neuronal membranes as a function of cholesterol concentration; phospholipid and phospholipid/cholesterol bilayers were also simulated to compare against available experimental data. Increased cholesterol concentrations compact and stiffen the lipid membrane, reducing permeability while modulating local water densities in the peri-membranous environment. Conversely, lower cholesterol mole fraction yields membranes with increased molecular disorder, enhanced fluidity, higher molecular tilting, and augmented interdigitation between bilayer leaflet lipids. Our findings provide a molecular insight on effect of cholesterol composition on various biochemical processes occurring at neuronal axon plasma membrane. These calculations also endeavor to establish a membrane-based link between cholesterol as an AD risk factor and possible AD pathology.