Citrullination of Amyloid-β Peptides in Alzheimer's Disease

Soumya Mukherjee, Keyla A. Perez, Celine Dubois, Rebecca M. Nisbet, Qiao Xin Li, Shiji Varghese, Liang Jin, Ian Birchall, Victor A. Streltsov, Laura J. Vella, Catriona McLean, Kevin J. Barham, Blaine R. Roberts, Colin L. Masters

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Protein citrullination (deimination of arginine residue) is a well-known biomarker of inflammation. Elevated protein citrullination has been shown to colocalize with extracellular amyloid plaques in postmortem AD patient brains. Amyloid-β (Aβ) peptides which aggregate and accumulate in the plaques of Alzheimer's disease (AD) have sequential N-terminal truncations and multiple post-translational modifications (PTM) such as isomerization, pyroglutamate formation, phosphorylation, nitration, and dityrosine cross-linking. However, no conclusive biochemical evidence exists whether citrullinated Aβ is present in AD brains. In this study, using high-resolution mass spectrometry, we have identified citrullination of Aβ in sporadic and familial AD brains by characterizing the tandem mass spectra of endogenous N-truncated citrullinated Aβ peptides. Our quantitative estimations demonstrate that ∼35% of pyroglutamate3-Aβ pool was citrullinated in plaques in the sporadic AD temporal cortex and ∼22% in the detergent-insoluble frontal cortex fractions. Similarly, hypercitrullinated pyroglutamate3-Aβ (∼30%) was observed in both the detergent-soluble as well as insoluble Aβ pool in familial AD cases. Our results indicate that a common mechanism for citrullination of Aβ exists in both the sporadic and familial AD. We establish that citrullination of Aβ is a remarkably common PTM, closely associated with pyroglutamate3-Aβ formation and its accumulation in AD. This may have implications for Aβ toxicity, autoantigenicity of Aβ, and may be relevant for the design of diagnostic assays and therapeutic targeting.

Original languageEnglish
Pages (from-to)3719-3732
Number of pages14
JournalACS Chemical Neuroscience
Issue number19
StatePublished - Oct 6 2021


  • Alzheimer's disease
  • amyloid-β (Aβ) peptides
  • citrullination
  • neuroinflammation
  • pyroglutamate-Aβ
  • tandem mass spectrometry


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