The N-terminus of amyloid-beta plays a crucial role in its aggregation and toxicity

• The aggregation of Amyloid Beta (Aß) peptide into insolubleamyloid fibrils that deposit in the brain is one of the primarypathogenic events in Alzheimer’s disease. We have previouslyshown, using a Drosophila model of Aß toxicity, that the N terminus of the Aß peptide, despite being unstructured in themature Aß fibril, nonetheless affects Aß induced neurodegeneration in vivo. In order to understand the contribution of the N terminusof Aß to its aggregation behaviour, we have investigated anumber of rationally designed N-terminal mutants in vitro. We find that single amino acid mutations in this region affect significantlythe kinetics of Aß aggregation in vitro as measured by arange of spectroscopic techniques. Furthermore, we observe striking differences in the morphology of the aggregated speciesformed by these different Aß mutants when imaged with TEM or  AFM  and  also  in the ß-sheet  content  of their  mature  fibrils. Interestingly, mutants with an increased net charge or lower hydrophobicity tend  to show slower aggregation  kinetics, and  to form more ordered  aggregates  whereas mutations that  reduce net charge   or   increase   hydrophobicity   favour   faster   aggregation kinetics   and   poorly   structured  aggregates.   In   addition,    the exposed  hydrophobicity of aggregates  formed  in the early stages of aggregation  is correlated  to their toxicity.  These findings demonstrate  not  only that  the N-terminus of the Aß peptide  plays a crucial  role  in its aggregation  and  toxicity  but  also  suggest that this  region  of Aß  may  modulate  in vivo toxicity  by altering  the conformations of aggregates that  it forms.

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