On the molecular mechanisms of the amyloid β-peptide aggregation

Research output: ThesisDoctoral Thesis (monograph)


The pathogenesis of Alzheimer’s disease is widely believed to be due to production and deposition of the amyloid β-peptide. Several variants of the Aβ peptide are known to exist in in vivo. Variations include mutations or additional functional groups attached to residue side chains and may affect the aggregation process. Early on-set Alzheimer’s is caused by a variety of single amino acid substitutions of the Aβ peptide.

The objectives of this thesis were to find a method to predict the aggregation propensity of Aβ40 variants and to understand the molecular mechanism of Aβ40 or Aβ42 peptide variants. We have extensively used thioflavin T-based fluorescence kinetic experiments to study the aggregation kinetics and the global analysis using the Amylofit platform to understand the molecular mechanism of aggregation of the variants. We showed that the aggregation propensity of Aβ40 variants can be predicted by monitoring the levels of inclusion body formation from peptides that are recombinantly expressed in E.coli cells. We could demonstrate that the net charge of a mutant greatly influences its aggregation propensity. We investigated the influence of various set of mutations on the aggregation mechanism of Aβ peptides. We showed that the aggregation behaviour is greatly modulated by the unstructured N-terminus of the Aβ peptide both in its 40- and 42-residue form. We could establish that specific residues at different positions in the primary sequence of Aβ40 peptide determined different stages of fibril formation. Especially, residues at positons 1, 7 and 13 of the Aβ40 peptide determined the specificity of secondary nucleation process of wild-type monomer. Besides this, we could confirm that the intact sequence of N-terminus is important in the aggregation process of Aβ42 peptide as reduced secondary nucleation rates were observed when residues at the N-terminus were scrambled. We addressed the influence of phosphorylation of two serine residues in the Aβ42 peptide on the aggregation process by designing single amino acid phosphomimic mutants. The rate of secondary nucleation is reduced more significantly for Ser26 substitutions than for Ser8 substitutions. Additionally, we found that Ser26 is a critical residue in the secondary nucleation of the Aβ42 peptide.


Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Other Chemistry Topics


  • protein aggregation, amyloid β-peptide, aggregation kinetics, aggregation mechanism N-terminus, mutations, variants, sequence determinants, cross-seeding
Original languageEnglish
Awarding Institution
Supervisors/Assistant supervisor
Award date2019 Mar 7
Place of PublicationLund
  • Lund University, Faculty of Science, Department of Chemistry
Print ISBNs978-91-7422-631-7
Electronic ISBNs978-91-7422-632-4
Publication statusPublished - 2019 Jan
Publication categoryResearch

Bibliographic note

Defence details Date: 2019-03-07 Time: 09:00 Place: Sal B Kemicentrum, Naturvetarvägen 14, Lund External reviewer(s) Name: Jemth, Per Title: Professor Affiliation: Uppsala universitet ---