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

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.

The Aβ and soluble amyloid precursor protein α (sAPPα) 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.

α-M significantly decreased Aβ₄₀ and Aβ₄₂ 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 IC₅₀ 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.

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.