title: A critical role for the self-assembly of Amyloid-β1-42 in neurodegeneration.
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.
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Marshall
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: Devkee M
authors.initials: DM
authors.lastname: Vadukul
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: Liza
authors.initials: L
authors.lastname: Dahal
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: Alina
authors.initials: A
authors.lastname: Theisen
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: Milena W
authors.initials: MW
authors.lastname: Fowler
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.|College of Sciences, Chemistry Department, Al-Mustansiriyah University, Baghdad, Iraq.
authors.forename: Youssra
authors.initials: Y
authors.lastname: Al-Hilaly
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: Lenzie
authors.initials: L
authors.lastname: Ford
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: György
authors.initials: G
authors.lastname: Kemenes
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Day
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Staras
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Serpell
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D058227:Amyloidogenic Proteins / Q000378:metabolism; D000686:Amyloidosis / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D008569:Memory Disorders / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D058227:Amyloidogenic Proteins; D010446:Peptide Fragments