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Formation of dynamic soluble surfactant-induced amyloid ? peptide aggregation intermediates.

ABSTRACT: Intermediate amyloidogenic states along the amyloid ? peptide (A?) aggregation pathway have been shown to be linked to neurotoxicity. To shed more light on the different structures that may arise during A? aggregation, we here investigate surfactant-induced A? aggregation. This process leads to co-aggregates featuring a ?-structure motif that is characteristic for mature amyloid-like structures. Surfactants induce secondary structure in A? in a concentration-dependent manner, from predominantly random coil at low surfactant concentration, via ?-structure to the fully formed ?-helical state at high surfactant concentration. The ?-rich state is the most aggregation-prone as monitored by thioflavin T fluorescence. Small angle x-ray scattering reveals initial globular structures of surfactant-A? co-aggregated oligomers and formation of elongated fibrils during a slow aggregation process. Alongside this slow (minutes to hours time scale) fibrillation process, much faster dynamic exchange (k(ex) ?1100 s(-1)) takes place between free and co-aggregate-bound peptide. The two hydrophobic segments of the peptide are directly involved in the chemical exchange and interact with the hydrophobic part of the co-aggregates. Our findings suggest a model for surfactant-induced aggregation where free peptide and surfactant initially co-aggregate to dynamic globular oligomers and eventually form elongated fibrils. When interacting with ?-structure promoting substances, such as surfactants, A? is kinetically driven toward an aggregation-prone state.

SUBMITTER: Abelein A

PROVIDER: S-EPMC5395029 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Formation of dynamic soluble surfactant-induced amyloid β peptide aggregation intermediates.

Abelein Axel A Kaspersen Jørn Døvling JD Nielsen Søren Bang SB Jensen Grethe Vestergaard GV Christiansen Gunna G Pedersen Jan Skov JS Danielsson Jens J Otzen Daniel E DE Gräslund Astrid A

The Journal of biological chemistry 20130617 32

Intermediate amyloidogenic states along the amyloid β peptide (Aβ) aggregation pathway have been shown to be linked to neurotoxicity. To shed more light on the different structures that may arise during Aβ aggregation, we here investigate surfactant-induced Aβ aggregation. This process leads to co-aggregates featuring a β-structure motif that is characteristic for mature amyloid-like structures. Surfactants induce secondary structure in Aβ in a concentration-dependent manner, from predominantly ...[more]

PMID: 23775077

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Project description:The misfolding and aggregation of amyloid-β (Aβ) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of Aβ1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against Aβ-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent Aβ peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic β-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-Aβ and TS2-Aβ systems also interpret different inhibitory effects on Aβ aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of Aβ inhibitors to prevent and disaggregate amyloid formation.

Dataset Information

Formation of dynamic soluble surfactant-induced amyloid ? peptide aggregation intermediates.

Publications

Formation of dynamic soluble surfactant-induced amyloid β peptide aggregation intermediates.

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