RESUMO
Amyloid-ß peptide (Aß)-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 Aß-induced toxicity and AD pathology. We investigate here the effect of curcumin on Aß40-induced toxicity in cultured human neuroblastoma SH-SY5Y cells and test a novel neuroprotection mechanism in which curcumin reduces Aß-membrane interactions and attenuates Aß-induced membrane disruptions. Predominantly monomeric Aß40 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 Aß into ß-sheet-enriched oligomers. Concomitantly, membrane morphology and lipid packing are disrupted. Curcumin dose-dependently ameliorates Aß-induced neurotoxicity and reduces either the rate or extent of Aß insertion into anionic lipid monolayers. Moreover, curcumin reduces Aß-induced dye leakage from lipid-bilayer-covered, dye-loaded, porous silica microspheres. Because curcumin neither affects the inherent surface activity of Aß nor modifies the membrane properties, it reduces Aß insertion by directly attenuating Aß-membrane interactions and reducing Aß-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 Aß-induced toxicity. Our work reveals a novel molecular mechanism by which curcumin reduces Aß-related pathology and toxicity and suggests a therapeutic strategy for preventing or treating AD by targeting the inhibition of Aß-induced membrane disruption.