α‐Mangostin decreases β‐amyloid peptides production via modulation of amyloidogenic pathway

Summary Aims β‐amyloid (Aβ) aggregation and deposition play a central role in the pathogenic process of Alzheimer's disease ( AD ). α‐Mangostin (α‐M), a polyphenolic xanthone, have been shown to dissociate Aβ oligomers. In this study, we further investigated the effect of α‐M on Aβ production and its molecular mechanism. Methods The Aβ and soluble amyloid precursor protein α ( sAPP α) in culture medium of cortical neurons were measured by ELISA . The activities of α‐, β‐, and γ‐secretases were assayed, and the interaction between α‐M and β‐ or γ‐secretases was simulated by molecular docking. Results α‐M significantly decreased Aβ 40 and Aβ 42 production. α‐M did not affect the expression of enzymes involved in nonamyloidogenic and amyloidogenic pathways, but significantly decreased the activities of β‐secretase and likely γ‐secretase with IC 50 13.22 nmol·L −1 and 16.98 nmol·L −1 , respectively. Molecular docking demonstrated that α‐M interacted with β‐site amyloid precursor protein cleaving enzyme 1 and presenilin 1 to interfere with their active sites. Conclusions Our data demonstrate that α‐M decreases Aβ production through inhibiting activities of β‐secretase and likely γ‐secretase in the amyloidogenic pathway. The current data together with previous study indicated that α‐M could be a novel neuroprotective agent through intervention of multiple pathological processes of AD .