α-Mangostin, a polyphenolic xanthone derivative from mangosteen, attenuates β-amyloid oligomers-induced neurotoxicity by inhibiting amyloid aggregation

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of beta-sheet-rich amyloid oligomers or fibrils which are associated with cellular toxicity in the brain. Inhibition of A beta aggregation could be a viable therapeutic strategy for slowing and/or preventing the progress of AD. Here we reported that alpha-mangostin (alpha-M), a polyphenolic xanthone derivative from mangosteen, concentration-dependently attenuated the neurotoxicity induced by A beta-(1-40) or A beta-(1-42) oligomers (EC50 = 3.89 nM, 4.14 nM respectively) as observed by decreased cell viability and impaired neurite outgrowth in primary rat cerebral cortical neurons. Molecular docking and dynamics simulations demonstrated that alpha-M could potentially bind to A beta and stabilize alpha-helical conformation. alpha-M was found to directly dissociate A beta-(1-40) and A beta-(1-42) oligomers by blotting with oligomer-specific antibodies. ThioflavinT fluorescence assay and electron microscopy imaging further demonstrated that alpha-M blocked the fibril formation as well as disturbed the pre-formed fibrils. Taken together, our results indicate that alpha-M is capable to inhibit and dissociate the A beta aggregation, which could contribute to its effect of attenuating A beta oligomers-induced neurotoxicity. Thus, alpha-M could be a great potential candidate for AD treatment. This article is part of a Special Issue entitled Post-Traumatic Stress Disorder'. (C) 2011 Elsevier Ltd. All rights reserved.