Effects of secondary metabolite extract from Phomopsis occulta on β-amyloid aggregation.

Haiqiang Wu,Liao Zhang,Neil Williamson,Alan Tunnacliffe,Yizhi Zheng,Jinyu Wang,Fang Zhang,Linkun An,Zeqiu Liang,Jie Jian

doi:10.1371/journal.pone.0109438

Haiqiang Wu, Liao Zhang + Show 8 more

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https://doi.org/10.1371/journal.pone.0109438

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Abstract

Inhibition of β-amyloid (Aβ) aggregation is an attractive therapeutic and preventive strategy for the discovery of disease-modifying agents in Alzheimer's disease (AD). Phomopsis occulta is a new, salt-tolerant fungus isolated from mangrove Pongamia pinnata (L.) Pierre. We report here the inhibitory effects of secondary metabolites from Ph. occulta on the aggregation of Aβ42. It was found that mycelia extracts (MEs) from Ph. occulta cultured with 0, 2, and 3 M NaCl exhibited inhibitory activity in an E. coli model of Aβ aggregation. A water-soluble fraction, ME0-W-F1, composed of mainly small peptides, was able to reduce aggregation of an Aβ42-EGFP fusion protein and an early onset familial mutation Aβ42E22G-mCherry fusion protein in transfected HEK293 cells. ME0-W-F1 also antagonized the cytotoxicity of Aβ42 in the neural cell line SH-SY5Y in dose-dependent manner. Moreover, SDS-PAGE and FT-IR analysis confirmed an inhibitory effect of ME0-W-F1 on the aggregation of Aβ42 in vitro. ME0-W-F1 blocked the conformational transition of Aβ42 from α-helix/random coil to β-sheet, and thereby inhibited formation of Aβ42 tetramers and high molecular weight oligomers. ME0-W-F1 and other water-soluble secondary metabolites from Ph. occulta therefore represent new candidate natural products against aggregation of Aβ42, and illustrate the potential of salt tolerant fungi from mangrove as resources for the treatment of AD and other diseases.

Highlights

Alzheimer’s disease (AD) is a devastating condition leading to progressive cognitive decline, functional impairment and loss of independence, and is the major cause of dementia in the elderly worldwide [1]
Marine microorganisms are a source of potentially useful natural extracts for the treatment of multifaceted diseases such as AD [21,22], and we focus here on microbes associated with mangroves, which are salt-tolerant, woody trees that grow in coastal habitats
Numerous chemical ligands have been developed as Ab aggregation inhibitors in recent years including Epigallocatechin gallate (EGCG) [34], curcumin [35], scyllo-inositol [36] and LPFFD [37], but very few have progressed to clinical trials

Summary

Introduction

Alzheimer’s disease (AD) is a devastating condition leading to progressive cognitive decline, functional impairment and loss of independence, and is the major cause of dementia in the elderly worldwide [1]. The molecular mechanism of its involvement in the development and progression of AD is not clear, a critical role for Ab is universally acknowledged [5]. Ab fibrils were once thought to be the main molecular culprit in AD, but recent studies show a more decisive correlation between the levels of soluble, non-fibrillar Ab oligomers and the extent of synaptic loss and cognitive impairment [6,7,8]. Compared with Ab fibrils and plaques, Ab oligomers are more potent as neurotoxins that cause disruption of neuronal synaptic plasticity [9,10]. The relationships between Ab peptides, oligomerisation, cellular dysfunction and AD suggest that inhibition of Ab oligomerisation might lead to novel therapeutics for the treatment of AD [11]

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