Quantification of N-terminal amyloid-β isoforms reveals isomers are the most abundant form of the amyloid-β peptide in sporadic Alzheimer's disease

Soumya Mukherjee, Keyla A. Perez, Larissa C. Lago, Stephan Klatt, Catriona A. McLean, Ian E. Birchall, Kevin J. Barnham, Colin L. Masters, Blaine R. Roberts

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Abstract

Plaques that characterize Alzheimer's disease accumulate over 20 years as a result of decreased clearance of amyloid-β peptides. Such long-lived peptides are subjected to multiple post-translational modifications, in particular isomerization. Using liquid chromatography ion mobility separations mass spectrometry, we characterized the most common isomerized amyloid-β peptides present in the temporal cortex of sporadic Alzheimer's disease brains. Quantitative assessment of amyloid-β N-terminus revealed that > 80% of aspartates (Asp-1 and Asp-7) in the N-terminus was isomerized, making isomerization the most dominant post-translational modification of amyloid-β in Alzheimer's disease brain. Total amyloid-β1-15 was ∼85% isomerized at Asp-1 and/or Asp-7 residues, with only 15% unmodified amyloid-β1-15 left in Alzheimer's disease. While amyloid-β4-15 the next most abundant N-terminus found in Alzheimer's disease brain, was only ∼50% isomerized at Asp-7 in Alzheimer's disease. Further investigations into different biochemically defined amyloid-β-pools indicated a distinct pattern of accumulation of extensively isomerized amyloid-β in the insoluble fibrillar plaque and membrane-associated pools, while the extent of isomerization was lower in peripheral membrane/vesicular and soluble pools. This pattern correlated with the accumulation of aggregation-prone amyloid-β42 in Alzheimer's disease brains. Isomerization significantly alters the structure of the amyloid-β peptide, which not only has implications for its degradation, but also for oligomer assembly, and the binding of therapeutic antibodies that directly target the N-terminus, where these modifications are located.

Original languageEnglish
Article numberfcab028
Number of pages17
JournalBrain Communications
Volume3
Issue number2
DOIs
Publication statusPublished - 2021
Externally publishedYes

Keywords

  • Alzheimer's disease
  • amyloid-β
  • isomerization
  • long-lived peptide
  • mass spectrometry
  • peptide

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