Dataset Information

Monitoring Alzheimer Amyloid Peptide Aggregation by EPR.

ABSTRACT: Plaques containing the aggregated beta-Amyloid (Abeta) peptide in the brain are the main indicators of Alzheimer's disease. Fibrils, the building blocks of plaques, can also be produced in vitro and consist of a regular arrangement of the peptide. The initial steps of fibril formation are not well understood and could involve smaller aggregates (oligomers) of Abeta. Such oligomers have even been implicated as the toxic agents. Here, a method to study oligomers on the time scale of aggregation is suggested. We have labeled the 40 residue Abeta peptide variant containing an N-terminal cysteine (cys-Abeta) with the MTSL [1-oxyl-2,2,5,5-tetramethyl-Delta-pyrroline-3-methyl] methanethiosulfonate spin label (SL-Abeta). Fibril formation in solutions of pure SL-Abeta and of SL-Abeta mixed with Abeta was shown by Congo-red binding and electron microscopy. Continuous-wave 9 GHz electron paramagnetic resonance reveals three fractions of different spin-label mobility: one attributed to monomeric Abeta, one to a multimer (8-15 monomers), and the last one to larger aggregates or fibrils. The approach, in principle, allows detection of oligomers on the time scale of aggregation.

SUBMITTER: Sepkhanova I

PROVIDER: S-EPMC2779421 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Monitoring Alzheimer Amyloid Peptide Aggregation by EPR.

Sepkhanova I I Drescher M M Meeuwenoord N J NJ Limpens R W A L RW Koning R I RI Filippov D V DV Huber M M

Applied magnetic resonance 20091031 2-4

Plaques containing the aggregated beta-Amyloid (Abeta) peptide in the brain are the main indicators of Alzheimer's disease. Fibrils, the building blocks of plaques, can also be produced in vitro and consist of a regular arrangement of the peptide. The initial steps of fibril formation are not well understood and could involve smaller aggregates (oligomers) of Abeta. Such oligomers have even been implicated as the toxic agents. Here, a method to study oligomers on the time scale of aggregation is ...[more]

PMID: 19946595

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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

Monitoring Alzheimer Amyloid Peptide Aggregation by EPR.

Publications

Monitoring Alzheimer Amyloid Peptide Aggregation by EPR.

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