srep30182.pdf (1.56 MB)
A critical role for the self-assembly of Amyloid-ß1-42 in neurodegeneration
journal contribution
posted on 2023-06-09, 02:03 authored by Karen MarshallKaren Marshall, Devkee M Vadukul, Liza Dahal, Alina Theisen, Milena W Fowler, Youssra Al-Hilaly, Lenzie Ford, George KemenesGeorge Kemenes, Iain Day, Kevin StarasKevin Staras, Louise SerpellLouise SerpellAmyloid ß1-42 (Aß1-42) 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 Aß1-42 (vAß1-42) differing in only two amino acids. Unlike Aß1-42, we found that the variant does not self-assemble, nor is it toxic to neuronal cells. Moreover, while Aß1-42 oligomers impact on synaptic function, vAß1-42 does not. In a living animal model system we demonstrate that only Aß1-42 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 Aß1-42 cellular studies of disease pathology, offering a new opportunity to decipher the mechanisms that accompany Aß1-42-induced toxicity leading to neurodegeneration.
Funding
Abeta-mediated toxicity in Alzheimer's disease: delineating mechanisms of internalisation, cell-cell transmission and synaptic dysfunction.; G1106; MRC-MEDICAL RESEARCH COUNCIL; MR/K022105/1
History
Publication status
- Published
File Version
- Published version
Journal
Scientific ReportsISSN
2045-2322Publisher
Nature Publishing GroupExternal DOI
Issue
1Volume
6Article number
a30182Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-07-06First Open Access (FOA) Date
2016-08-09First Compliant Deposit (FCD) Date
2016-07-06Usage metrics
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