[alpha]-Mangostin decreases [beta]-amyloid peptides production via modulation of amyloidogenic pathway

• Published in: CNS neuroscience & therapeutics Vol. 23; no. 6; p. 526
• Main Authors: Zhao, Lan-Xue, Wang, Yan, Liu, Ting, Wang, Yan-Xia, Chen, Hong-Zhuan, Xu, Jian-Rong, Qiu, Yu
• Format: Journal Article
• Language: English
• Published: Oxford John Wiley & Sons, Inc 01.06.2017
• Subjects: Alzheimer's disease; Amyloid precursor protein; Amyloidogenesis; Enzyme-linked immunosorbent assay; Enzymes; Neurodegenerative diseases; Neuroprotection; Presenilin 1; Secretase; β-Amyloid
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12699

Summary Aims [beta]-amyloid (A[beta]) aggregation and deposition play a central role in the pathogenic process of Alzheimer's disease (AD). [alpha]-Mangostin ([alpha]-M), a polyphenolic xanthone, have been shown to dissociate A[beta] oligomers. In this study, we further investigated the effect of [alpha]-M on A[beta] production and its molecular mechanism. Methods The A[beta] and soluble amyloid precursor protein [alpha] (sAPP[alpha]) in culture medium of cortical neurons were measured by ELISA. The activities of [alpha]-, [beta]-, and [gamma]-secretases were assayed, and the interaction between [alpha]-M and [beta]- or [gamma]-secretases was simulated by molecular docking. Results [alpha]-M significantly decreased A[beta]40 and A[beta]42 production. [alpha]-M did not affect the expression of enzymes involved in nonamyloidogenic and amyloidogenic pathways, but significantly decreased the activities of [beta]-secretase and likely [gamma]-secretase with IC50 13.22 nmol·L-1 and 16.98 nmol·L-1, respectively. Molecular docking demonstrated that [alpha]-M interacted with [beta]-site amyloid precursor protein cleaving enzyme 1 and presenilin 1 to interfere with their active sites. Conclusions Our data demonstrate that [alpha]-M decreases A[beta] production through inhibiting activities of [beta]-secretase and likely [gamma]-secretase in the amyloidogenic pathway. The current data together with previous study indicated that [alpha]-M could be a novel neuroprotective agent through intervention of multiple pathological processes of AD.