Effects of Secondary Metabolite Extract from Phomopsis occulta on β-Amyloid Aggregation

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.

Antiaggregation Potential of Padina gymnospora against the Toxic Alzheimer’s Beta-Amyloid Peptide 25–35 and Cholinesterase Inhibitory Property of Its Bioactive Compounds

“…Many chemical ligands have been developed as Aβ aggregation inhibitors in recent years including Curcumin and scyllo-inositol [ 13 , 28 ] but very few have progressed to clinical trials. Considering this disappointing situation, it is appropriate to search for alternative Aβ aggregation inhibitors among natural products.…”

“…Considering this disappointing situation, it is appropriate to search for alternative Aβ aggregation inhibitors among natural products. Some fungal and plant extracts have remarkable anti-AD activities in vitro and in vivo due to the inhibition of Aβ aggregation [ 13 ]. Durairajan et al reported that Salvianolic acid B (Sal B) derived from Salvia miltiorrhiza , a Chinese herbal medicine commonly used for the treatment of cardiovascular and cerebrovascular disorders, has been found to possess inhibitory effect on Aβ fibrillation and disaggregation of fibrils [ 29 ].…”

“…Although the involvement of its molecular mechanism in development and progression of AD is not clear, a critical role of Aβ is universally accepted [ 11 ]. Apart from forming plaques, the Aβ oligomers are also more effective as neurotoxins that cause disruption of neuronal synaptic plasticity, which suggest that, inhibition of Aβ oligomerisation might lead to novel therapeutic method for AD treatment [ 12 , 13 ] Recent reports illustrated that oxidative stress also plays a significant role in AD pathogenesis and Aβ peptides have been proposed as a source of oxidative stress. Oxidative stress induced by Aβ leads to increased oxidative modification of proteins and lipids which in turn leads to impaired cellular function, cell death and consequently cognitive decline and AD pathology [ 14 ].…”

Alleviation of Memory Deficit by Bergenin via the Regulation of Reelin and Nrf-2/NF-κB Pathway in Transgenic Mouse Model

“…Memory impairment and cognitive decline are associated with AD, a well-known neurological disorder. The toxic events involved in the pathogenesis of spatial memory deficit in AD include multiple biological processes such as Aβ aggregation, neurofibrillary tangles formation, neuroinflammation, and oxidative stress linked to neurodegenerative diseases [ 19 ]. Inhibition of Aβ aggregation is a promising therapeutic approach towards the identification of disease-modifying therapy against AD.…”

Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

“…Alpha-synuclein-EYFP was then cloned into the pLJM1 backbone for lentiviral expression (Addgene: 19319). pLJM1-EGFP was a gift from David Sabatini Flp-InTM T-RExTM 293 cell line (Invitrogen), a derivative of HEK293 cells containing a stably integrated FRT site and a TetR repressor, was used to generate stable cell lines expressing either mCherry or Aβ42-mCherry (pcDNA3.3-mCherry, pcDNA3.3-Ab42-mCherry) under the Flp-InTM expression vector as described previously (46,77). Cells were maintained in DMEM high glucose media (Sigma-Aldrich) supplemented with 10% fetal bovine serum (FBS), 2 mM glutaMAX, and 1 % antibioticantimycotic (all Thermo Fisher Scientific).…”