The N-terminus of amyloid-beta plays a crucial role in its aggregation and toxicity
2010 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 277, no Suppl. 1, 79-80 p.Article in journal, Meeting abstract (Other academic) Published
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.
Place, publisher, year, edition, pages
Wiley-Blackwell, 2010. Vol. 277, no Suppl. 1, 79-80 p.
Engineering and Technology
IdentifiersURN: urn:nbn:se:liu:diva-58958ISI: 000278565100287OAI: oai:DiVA.org:liu-58958DiVA: diva2:347785
35th Congress of the Federation-of-European-Biochemical-Societies, Gothenburg, Sweden, June 26-July 01, 2010