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Structure-activity relationships in peptide modulators of ?-amyloid protein aggregation: variation in ?,?-disubstitution results in altered aggregate size and morphology.

ABSTRACT: Neuronal cytotoxicity observed in Alzheimer's disease (AD) is linked to the aggregation of ?-amyloid peptide (A?) into toxic forms. Increasing evidence points to oligomeric materials as the neurotoxic species, not A? fibrils; disruption or inhibition of A? self-assembly into oligomeric or fibrillar forms remains a viable therapeutic strategy to reduce A? neurotoxicity. We describe the synthesis and characterization of amyloid aggregation mitigating peptides (AAMPs) whose structure is based on the A? "hydrophobic core" A?(17-20), with ?,?-disubstituted amino acids (??AAs) added into this core as potential disrupting agents of fibril self-assembly. The number, positional distribution, and side-chain functionality of ??AAs incorporated into the AAMP sequence were found to influence the resultant aggregate morphology as indicated by ex situ experiments using atomic force microscopy (AFM) and transmission electron microscopy (TEM). For instance, AAMP-5, incorporating a sterically hindered ??AA with a diisobutyl side chain in the core sequence, disrupted A?(1-40) fibril formation. However, AAMP-6, with a less sterically hindered ??AA with a dipropyl side chain, altered fibril morphology, producing shorter and larger sized fibrils (compared with those of A?(1-40)). Remarkably, ??AA-AAMPs caused disassembly of existing A? fibrils to produce either spherical aggregates or protofibrillar structures, suggesting the existence of equilibrium between fibrils and prefibrillar structures.

SUBMITTER: Bett CK

PROVIDER: S-EPMC3368689 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Structure-activity relationships in peptide modulators of β-amyloid protein aggregation: variation in α,α-disubstitution results in altered aggregate size and morphology.

Bett Cyrus K CK Ngunjiri Johnpeter N JN Serem Wilson K WK Fontenot Krystal R KR Hammer Robert P RP McCarley Robin L RL Garno Jayne C JC

ACS chemical neuroscience 20100708 9

Neuronal cytotoxicity observed in Alzheimer's disease (AD) is linked to the aggregation of β-amyloid peptide (Aβ) into toxic forms. Increasing evidence points to oligomeric materials as the neurotoxic species, not Aβ fibrils; disruption or inhibition of Aβ self-assembly into oligomeric or fibrillar forms remains a viable therapeutic strategy to reduce Aβ neurotoxicity. We describe the synthesis and characterization of amyloid aggregation mitigating peptides (AAMPs) whose structure is based on th ...[more]

PMID: 22778850

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Project description:The misfolding and aggregation of amyloid-? (A?) 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 A?1-42 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 A?-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent A? peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic ?-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-A? and TS2-A? systems also interpret different inhibitory effects on A? 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 A? inhibitors to prevent and disaggregate amyloid formation.

Dataset Information

Structure-activity relationships in peptide modulators of ?-amyloid protein aggregation: variation in ?,?-disubstitution results in altered aggregate size and morphology.

Publications

Structure-activity relationships in peptide modulators of β-amyloid protein aggregation: variation in α,α-disubstitution results in altered aggregate size and morphology.

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