The Aggregation Paths and Products of Aβ42 Dimers Are Distinct from Those of the Aβ42 Monomer

Research output: Contribution to journalArticle

Abstract

Extracts of Alzheimer's disease (AD) brain that contain what appear to be sodium dodecyl sulfate-stable amyloid β-protein (Aβ) dimers potently block LTP and impair memory consolidation. Brain-derived dimers can be physically separated the Aβ monomer, consist primarily of Aβ42, and resist denaturation by chaotropic agents. In nature, covalently cross-linked Aβ dimers could be generated in two ways: by the formation of a dityrosine (DiY) or an isopeptide ϵ-(γ-glutamyl)-lysine (Q-K) bond. We enzymatically cross-linked recombinant Aβ42 monomer to produce DiY and Q-K dimers and then used a range of biophysical methods to study their aggregation. Both Q-K and DiY dimers aggregate to form soluble assemblies distinct from the fibrillar aggregates formed by the Aβ monomer. The results suggest that the cross-links disfavor fibril formation from Aβ dimers, thereby enhancing the concentration of soluble aggregates akin to those in aqueous extracts of AD brain. Thus, it seems that Aβ dimers may play an important role in determining the formation of soluble rather than insoluble aggregates.

Details

Authors
  • Tiernan T. O'Malley
  • William M. Witbold
  • Sara Linse
  • Dominic M. Walsh
Organisations
External organisations
  • Harvard University
  • University College Dublin
  • Wyatt Technology Corporation
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biochemistry and Molecular Biology
  • Medicinal Chemistry
Original languageEnglish
Pages (from-to)6150-6161
Number of pages12
JournalBiochemistry
Volume55
Issue number44
Publication statusPublished - 2016 Nov 8
Publication categoryResearch
Peer-reviewedYes