Design of non-aggregating variants of Aβ peptide

• Published in: Biochemical and biophysical research communications 2014-10, Vol.453 (3), p.449-454
• Main Authors: Caine, Joanne M, Churches, Quentin, Waddington, Lynne, Nigro, Julie, Breheney, Kerry, Masters, Colin L, Nuttall, Stewart D, Streltsov, Victor A
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; AGGLOMERATION; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animals; ELECTRON MICROSCOPY; FILTRATION; GELS; GROWTH FACTORS; LIGHT SCATTERING; Microscopy, Electron, Scanning; MOLECULAR WEIGHT; Mutation; MUTATIONS; NERVOUS SYSTEM DISEASES; PC12 Cells; PEPTIDES; Peptides - chemistry; Peptides - metabolism; Rats; RESIDUES; Thiazoles - metabolism; TOXICITY
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.09.102

Self association of the amyloid-β (Aβ42) peptide into oligomers, high molecular weight forms, fibrils and ultimately neuritic plaques, has been correlated with progressive cognitive decline in Alzheimer's disease. Thus, insights into the drivers of the aggregation pathway have the capacity to significantly contribute to our understanding of disease mechanism. Functional assays and a three-dimensional crystal structure of the P3 amyloidogenic region 18-41 of Aβ were used to identify residues important in self-association and to design novel non-aggregating variants of the peptide. Biophysical studies (gel filtration, SDS-PAGE, dynamic light scattering, thioflavin T assay, and electron microscopy) demonstrate that in contrast to wild type Aβ these targeted mutations lose the ability to self-associate. Loss of aggregation also correlates with reduced neuronal toxicity. Our results highlight residues and regions of the Aβ peptide important for future targeting agents aimed at the amelioration of Alzheimer's disease.