Citrullination of Amyloid-β peptides in Alzheimer's disease
- Author(s)
- Mukherjee, S; Perez, KA; Dubois, C; Nisbet, RM; Li, QX; Varghese, S; Jin, L; Birchall, I; Streltsov, VA; Vella, LJ; McLean, C; Barham, KJ; Roberts, BR; Masters, CL;
- Journal Title
- ACS Chemical Neuroscience
- Publication Type
- epub ahead of print
- Abstract
- 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.
- Publisher
- ACS
- Keywords
- Alzheimer’s disease; amyloid-β (Aβ) peptides; citrullination; neuroinflammation; pyroglutamate-Aβ; tandem mass spectrometry
- Research Division(s)
- Population Health And Immunity
- PubMed ID
- 34519476
- Publisher's Version
- https://doi.org/10.1021/acschemneuro.1c00474
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-09-17 11:23:22
Last Modified: 2021-09-17 11:56:37