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Lookup NU author(s): Professor Raj KalariaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023 The Authors. Published under the terms of the CC BY 4.0 license. Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age-linked damage to amino acid sequence NGR (Asn-Gly-Arg) results in “gain-of-function” conformational switching to isoDGR (isoAsp-Gly-Arg). This integrin-binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy mitigates lifespan reduction of Pcmt1−/− mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1−/− and naturally aged WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1 mg/kg) was sufficient to significantly reduce isoDGR-protein levels in body tissues, decreased pro-inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1−/− mice. Mechanistically, isoDGR-mAb mediated immune clearance of damaged isoDGR-proteins via antibody-dependent cellular phagocytosis (ADCP). These results indicate that immunotherapy targeting age-linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders.
Author(s): Kalailingam P, Mohd-Kahliab K-H, Ngan SC, Iyappan R, Melekh E, Lu T, Zien GW, Sharma B, Guo T, MacNeil AJ, MacPherson REK, Tsiani EL, O'Leary DD, Lim KL, Su IH, Gao Y-G, Richards AM, Kalaria RN, Chen CP, McCarthy NE, Sze SK
Publication type: Article
Publication status: Published
Journal: EMBO Molecular Medicine
Year: 2023
Volume: 15
Issue: 12
Print publication date: 07/12/2023
Online publication date: 16/11/2023
Acceptance date: 31/10/2023
Date deposited: 04/03/2024
ISSN (print): 1757-4676
ISSN (electronic): 1757-4684
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.15252/emmm.202318526
DOI: 10.15252/emmm.202318526
PubMed id: 37971164
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