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Title: Design of non-aggregating variants of Aβ peptide

Abstract

Highlights: • Non-aggregating, non-toxic variants of Aβ peptide were designed using Aβ structure. • Mutations reduce aggregation by stabilising Aβ into small non-toxic oligomers. • Identification of these residues will assist the design of future therapeutic peptides. - Abstract: Self association of the amyloid-β (Aβ{sub 42}) 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:
;  [1]; ;  [1];  [2];  [1]
  1. CSIRO Materials Science and Engineering, 343 Royal Parade, Parkville, Victoria 3052 (Australia)
  2. CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053 (Australia)
Publication Date:
OSTI Identifier:
22416797
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 453; Journal Issue: 3; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AGGLOMERATION; ELECTRON MICROSCOPY; FILTRATION; GELS; GROWTH FACTORS; LIGHT SCATTERING; MOLECULAR WEIGHT; MUTATIONS; NERVOUS SYSTEM DISEASES; PEPTIDES; RESIDUES; TOXICITY

Citation Formats

Caine, Joanne M., E-mail: jo.caine@csiro.au, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Churches, Quentin, Waddington, Lynne, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Nigro, Julie, Breheney, Kerry, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Masters, Colin L., Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria 3052, Nuttall, Stewart D., Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Streltsov, Victor A., E-mail: victor.streltsov@csiro.au, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, and CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053. Design of non-aggregating variants of Aβ peptide. United States: N. p., 2014. Web. doi:10.1016/J.BBRC.2014.09.102.
Caine, Joanne M., E-mail: jo.caine@csiro.au, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Churches, Quentin, Waddington, Lynne, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Nigro, Julie, Breheney, Kerry, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Masters, Colin L., Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria 3052, Nuttall, Stewart D., Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Streltsov, Victor A., E-mail: victor.streltsov@csiro.au, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, & CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053. Design of non-aggregating variants of Aβ peptide. United States. doi:10.1016/J.BBRC.2014.09.102.
Caine, Joanne M., E-mail: jo.caine@csiro.au, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Churches, Quentin, Waddington, Lynne, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Nigro, Julie, Breheney, Kerry, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Masters, Colin L., Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria 3052, Nuttall, Stewart D., Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053, Streltsov, Victor A., E-mail: victor.streltsov@csiro.au, Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, and CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053. Fri . "Design of non-aggregating variants of Aβ peptide". United States. doi:10.1016/J.BBRC.2014.09.102.
@article{osti_22416797,
title = {Design of non-aggregating variants of Aβ peptide},
author = {Caine, Joanne M., E-mail: jo.caine@csiro.au and Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052 and CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053 and Churches, Quentin and Waddington, Lynne and Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052 and Nigro, Julie and Breheney, Kerry and Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052 and CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053 and Masters, Colin L. and Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria 3052 and Nuttall, Stewart D. and Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052 and CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053 and Streltsov, Victor A., E-mail: victor.streltsov@csiro.au and Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052 and CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053},
abstractNote = {Highlights: • Non-aggregating, non-toxic variants of Aβ peptide were designed using Aβ structure. • Mutations reduce aggregation by stabilising Aβ into small non-toxic oligomers. • Identification of these residues will assist the design of future therapeutic peptides. - Abstract: Self association of the amyloid-β (Aβ{sub 42}) 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.},
doi = {10.1016/J.BBRC.2014.09.102},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 453,
place = {United States},
year = {2014},
month = {10}
}