Membrane-Mediated Neuroprotection by Curcumin from Amyloid-beta-Peptide-Induced Toxicity

Amyloid-beta peptide (A beta)-membrane interactions have been implicated in the formation of toxic oligomers that permeabilize membranes, allowing an influx of calcium ions and triggering cell death in the pathogenesis of Alzheimer's disease (AD). Curcumin, a small dietary polyphenolic molecule, has been shown to reduce A beta-induced toxicity and AD pathology. We investigate here the effect of curcumin on A beta 40-induced toxicity in cultured human neuroblastoma SH-SY5Y cells and test a novel neuroprotection mechanism in which curcumin reduces A beta-membrane interactions and attenuates A beta-induced membrane disruptions. Predominantly monomeric A beta 40 exerts toxicity toward SH-SY5Y cells and has been shown to insert spontaneously into anionic lipid monolayers at the air/water interface, resulting in the misfolding and assembly of A beta into beta-sheet-enriched oligomers. Concomitantly, membrane morphology and lipid packing are disrupted. Curcumin dose-dependently ameliorates A beta-induced neurotoxicity and reduces either the rate or extent of A beta insertion into anionic lipid monolayers. Moreover, curcumin reduces A beta-induced dye leakage from lipid-bilayer-covered, dye-loaded, porous silica microspheres. Because curcumin neither affects the inherent surface activity of A beta nor modifies the membrane properties, it reduces A beta insertion by directly attenuating A beta-membrane interactions and reducing A beta-induced membrane disruption. Although the exact molecular mechanism of curcumin's membrane protective effect remains unclear, this effect could in part contribute to curcumin's neuroprotective effect with respect to A beta-induced toxicity. Our work reveals a novel molecular mechanism by which curcumin reduces A beta-related pathology and toxicity and suggests a therapeutic strategy for preventing or treating AD by targeting the inhibition of A beta-induced membrane disruption.