title: Α-mangostin, a polyphenolic xanthone derivative from mangosteen, attenuates β-amyloid oligomers-induced neurotoxicity by inhibiting amyloid aggregation.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of β-sheet-rich amyloid oligomers or fibrils which are associated with cellular toxicity in the brain. Inhibition of Aβ aggregation could be a viable therapeutic strategy for slowing and/or preventing the progress of AD. Here we reported that α-mangostin (α-M), a polyphenolic xanthone derivative from mangosteen, concentration-dependently attenuated the neurotoxicity induced by Aβ-(1-40) or Aβ-(1-42) oligomers (EC(50) = 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 α-M could potentially bind to Aβ and stabilize α-helical conformation. α-M was found to directly dissociate Aβ-(1-40) and Aβ-(1-42) oligomers by blotting with oligomer-specific antibodies. ThioflavinT fluorescence assay and electron microscopy imaging further demonstrated that α-M blocked the fibril formation as well as disturbed the pre-formed fibrils. Taken together, our results indicate that α-M is capable to inhibit and dissociate the Aβ aggregation, which could contribute to its effect of attenuating Aβ oligomers-induced neurotoxicity. Thus, α-M could be a great potential candidate for AD treatment. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.forename: Jian-Rong
authors.initials: JR
authors.lastname: Xu
authors.forename: Yan-Xia
authors.initials: YX
authors.lastname: Wang
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Hou
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiu
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D051381:Rats; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D044004:Xanthones; C078592:amyloid beta-protein (1-40); C021053:mangostin