A critical role for the self-assembly of Amyloid-ß1-42 in neurodegeneration

Amyloid 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.