Amyloid-beta oligomerization is associated with the generation of a typical peptide fragment fingerprint

Alzheimers Dement. 2016 Sep;12(9):996-1013. doi: 10.1016/j.jalz.2016.03.011. Epub 2016 Apr 26.

Abstract

Amyloid-beta (Aβ) peptide oligomerization plays a central role in the pathogenesis of Alzheimer's disease (AD), and Aβ oligomers are collectively considered an appealing therapeutic target for the treatment of AD. However, the molecular mechanisms leading to the pathologic accumulation of oligomers are unclear, and the exact structural composition of oligomers is being debated. Using targeted and quantitative mass spectrometry, we reveal site-specific Aβ autocleavage during the early phase of aggregation, producing a typical Aβ fragment signature and that truncated Aβ peptides can form stable oligomeric complexes with full-length Aβ peptide. We show that the use of novel anti-Aβ antibodies raised against these truncated Aβ isoforms allows for monitoring and targeting the accumulation of truncated Aβ fragments. Antibody-enabled screening of transgenic models of AD as well as human postmortem brain tissue and cerebrospinal fluid revealed that aggregation-associated Aβ cleavage is a highly relevant clinical feature of AD.

Keywords: Aggregation; Alzheimer's disease; Autocleavage; C-terminal amidation; Mass spectrometry; Oligomers; Selected reaction monitoring.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Autoantibodies
  • Brain / metabolism
  • Chromatography, Gel
  • Chromatography, Liquid
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Immunoblotting
  • Mass Spectrometry
  • Mice, Transgenic
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Protein Aggregation, Pathological / metabolism*
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Multimerization
  • Protein Structure, Secondary

Substances

  • Amyloid beta-Peptides
  • Autoantibodies
  • Peptide Fragments
  • Protein Isoforms
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)