Increased Secondary Nucleation Underlies Accelerated Aggregation of the Four-Residue N-Terminally Truncated Aβ42 Species Aβ5-42

Research output: Contribution to journalArticle

Abstract

Aggregation of the amyloid-β (Aβ) peptide into plaques is believed to play a crucial role in Alzheimer's disease. Amyloid plaques consist of fibrils of full length Aβ peptides as well as N-terminally truncated species. β-Site amyloid precursor protein-cleaving enzyme (BACE1) cleaves amyloid precursor protein in the first step in Aβ peptide production and is an attractive therapeutic target to limit Aβ generation. Inhibition of BACE1, however, induces a unique pattern of Aβ peptides with increased levels of N-terminally truncated Aβ peptides starting at position 5 (Aβ5-X), indicating that these peptides are generated through a BACE1-independent pathway. Here we elucidate the aggregation mechanism of Aβ5-42 and its influence on full-length Aβ42. We find that, compared to Aβ42, Aβ5-42 is more aggregation prone and displays enhanced nucleation rates. Aβ5-42 oligomers cause nonspecific membrane disruption to similar extent as Aβ42 but appear at earlier time points in the aggregation reaction. Noteworthy, this implies similar toxicity of Aβ42 and Aβ5-42 and the toxic species are generated faster by Aβ5-42. The increased rate of secondary nucleation on the surface of existing fibrils originates from a higher affinity of Aβ5-42 monomers for fibrils, as compared to Aβ42: an effect that may be related to the reduced net charge of Aβ5-42. Moreover, Aβ5-42 and Aβ42 peptides coaggregate into heteromolecular fibrils and either species can elongate existing Aβ42 or Aβ5-42 fibrils but Aβ42 fibrils are more catalytic than Aβ5-42 fibrils. Our findings highlight the importance of the N-terminus for surface-catalyzed nucleation and thus the production of toxic oligomers.

Details

Authors
  • Tanja Weiffert
  • Georg Meisl
  • Patrick Flagmeier
  • Suman De
  • Christopher J.R. Dunning
  • Birgitta Frohm
  • Henrik Zetterberg
  • Kaj Blennow
  • Erik Portelius
  • David Klenerman
  • Christopher M. Dobson
  • Tuomas P.J. Knowles
  • Sara Linse
Organisations
External organisations
  • University of Cambridge
  • Sahlgrenska University Hospital
  • University College London
  • University of Gothenburg
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry
  • Neurosciences

Keywords

  • aggregation mechanism, Alzheimer, BACE, coaggregation, Misfolding, toxicity
Original languageEnglish
JournalACS Chemical Neuroscience
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes