skip to main content

SciTech ConnectSciTech Connect

Title: Design of non-aggregating variants of Aβ peptide

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] ;  [2] ;  [2] ; ;  [1] ;  [2] ; ;  [1] ;  [2] ;  [2] ;  [3] ;  [2] ;  [1] ;  [2] ;  [2] ;  [1] ;  [2] ;  [2]
  1. CSIRO Materials Science and Engineering, 343 Royal Parade, Parkville, Victoria 3052 (Australia)
  2. (Australia)
  3. CRC for Mental Health, Level 2, 161 Barry Street, Carlton South, Victoria 3053 (Australia)
Publication Date:
OSTI Identifier:
22416797
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; 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)
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