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?-Mangostin decreases ?-amyloid peptides production via modulation of amyloidogenic pathway.

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

SUBMITTER: Zhao LX

PROVIDER: S-EPMC6492755 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Zhao Lan-Xue LX Wang Yan Y Liu Ting T Wang Yan-Xia YX Chen Hong-Zhuan HZ Xu Jian-Rong JR Qiu Yu Y

CNS neuroscience & therapeutics 20170421 6

<h4>Aims</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 28429536

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Project description:The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer's disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by β- and γ-secretases in the 'amyloidogenic' proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the 'non-amyloidogenic' pathway which, through the action of the α-secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting β-secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the β-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression/activity of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer's disease.

Dataset Information

?-Mangostin decreases ?-amyloid peptides production via modulation of amyloidogenic pathway.

Publications

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

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