Aggregation and toxicity of amyloid-beta peptide in relation to peptide sequence variation

A. Vandersteen

Research output: ThesisPhD Thesis - Research UT, graduation UT

142 Downloads (Pure)

Abstract

Generally, aggregation of the amyloid-ß peptide is considered the cause of neuronal death in Alzheimer disease. The heterogenous Aß peptide occurs in various lengths in vivo: Aß40 and Aß42 are the predominant forms while both shorter and longer peptides exist. Aß40 and shorter isoforms are less aggregation-prone and hence considered less dangerous than Aß42 and longer isoforms, which are more aggregation-prone. Up to now research mainly focussed on the predominant Aß peptides and their individual characterization. This work emphasizes on the behavior of various isoforms in mixtures, as to mimick the in vivo situation. The results indicate that subtle differences in the ratio of Aß40 to Aß42 can induces strong differences in aggregation behavior and toxicity. This observation is not limited to these isoforms: a small fraction of the shorter Aß38 or the longer Aß43 affects the aggregation behavior of the predominant Aß isoforms. Additionally these minor peptides can enhance the toxic effects of Aß40 on neurons while damping that of Aß42. This is crucial for the development of new therapeutics as current strategies aim to decrease the production of Aß42 while increasing Aß38 levels at the same time. The strategy is based on the assumption that the presence of less aggregating Aß38 is less hazardous than that of Aß42. The results presented here however suggest that the situation is more nuanced. A detailed understanding of the agggregation behavior of less predominant Aß isoforms, in isolation but certainly in mixtures, will lead to better insight in the mechanisms leading to Alzheimer disease and as such contribute to improved therapeutic approaches.
Original languageEnglish
Awarding Institution
  • University of Twente
Supervisors/Advisors
  • Subramaniam, Vinod, Supervisor
  • Broersen, Kerensa , Advisor
  • Rousseau, F., Supervisor
  • Remaut, H., Supervisor
  • Schymkowitz, J., Advisor
Award date12 Dec 2012
Place of PublicationEnschede
Publisher
Print ISBNs978-90-365-3481-9
DOIs
Publication statusPublished - 12 Dec 2012

Keywords

  • IR-81970
  • METIS-288677

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