A critical role for the self-assembly of Amyloid-β1-42 in neurodegeneration

Marshall, Karen E, Vadukul, Devkee M, Dahal, Liza, Theisen, Alina, Fowler, Milena W, Al-Hilaly, Youssra, Ford, Lenzie, Kemenes, György, Day, Iain J, Staras, Kevin and Serpell, Louise (2016) A critical role for the self-assembly of Amyloid-β1-42 in neurodegeneration. Scientific Reports, 6. ISSN 2045-2322

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Abstract

Amyloid β1-42 (Aβ1-42) plays a central role in Alzheimer’s disease. The link between structure, assembly and neuronal toxicity of this peptide is of major current interest but still poorly defined. Here, we explored this relationship by rationally designing a variant form of Aβ1-42 (vAβ1-42) differing in only two amino acids. Unlike Aβ1-42, we found that the variant does not self-assemble, nor is it toxic to neuronal cells. Moreover, while Aβ1-42 oligomers impact on synaptic function, vAβ1-42 does not. In a living animal model system we demonstrate that only Aβ1-42 leads to memory deficits. Our findings underline a key role for peptide sequence in the ability to assemble and form toxic structures. Furthermore, our non-toxic variant satisfies an unmet demand for a closely related control peptide for Aβ1-42 cellular studies of disease pathology, offering a new opportunity to decipher the mechanisms that accompany Aβ1-42-induced toxicity leading to neurodegeneration.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Louise Serpell
Date Deposited: 06 Jul 2016 10:22
Last Modified: 15 Aug 2017 10:17
URI: http://sro.sussex.ac.uk/id/eprint/61902

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Project NameSussex Project NumberFunderFunder Ref
Abeta-mediated toxicity in Alzheimer's disease: delineating mechanisms of internalisation, cell-cell transmission and synaptic dysfunction.G1106MRC-MEDICAL RESEARCH COUNCILMR/K022105/1