title: Design of non-aggregating variants of Aβ peptide.
abstract: 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.
authors.affiliation: CSIRO Materials Science and Engineering, 343 Royal Parade, Parkville, Victoria 3052, Australia; Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Australia; CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Australia. Electronic address: jo.caine@csiro.au.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Caine
authors.affiliation: CSIRO Materials Science and Engineering, 343 Royal Parade, Parkville, Victoria 3052, Australia; Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Churches
authors.affiliation: CSIRO Materials Science and Engineering, 343 Royal Parade, Parkville, Victoria 3052, Australia; Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Lynne
authors.initials: L
authors.lastname: Waddington
authors.affiliation: CSIRO Materials Science and Engineering, 343 Royal Parade, Parkville, Victoria 3052, Australia; Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Australia; CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Australia.
authors.forename: Julie
authors.initials: J
authors.lastname: Nigro
authors.affiliation: CSIRO Materials Science and Engineering, 343 Royal Parade, Parkville, Victoria 3052, Australia; Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Australia; CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Australia.
authors.forename: Kerry
authors.initials: K
authors.lastname: Breheney
authors.affiliation: CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Australia; Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: CSIRO Materials Science and Engineering, 343 Royal Parade, Parkville, Victoria 3052, Australia; Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Australia; CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Australia.
authors.forename: Stewart D
authors.initials: SD
authors.lastname: Nuttall
authors.affiliation: CSIRO Materials Science and Engineering, 343 Royal Parade, Parkville, Victoria 3052, Australia; Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Australia; CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Australia. Electronic address: victor.streltsov@csiro.au.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Streltsov
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D008855:Microscopy, Electron, Scanning; D009154:Mutation; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D013844:Thiazoles / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010455:Peptides; D013844:Thiazoles; C009462:thioflavin T
keywords: Alzheimer’s disease; Amyloid beta; Non-aggregating mutations