Age-impaired remyelination is associated with dysregulated microglial transitions
Multiple sclerosis (MS) is a chronic, inflammatory condition characterized by neurodegeneration and lost myelin, or demyelination. This lost myelin may be regenerated in people with MS through a process called remyelination, that is prone to failure and is impaired with age. Remyelination is facilitated by microglia but our understanding of the microglial response during remyelination is incomplete. Here, we profile the microglial response during remyelination in the lysolecithin mouse model using single-cell RNA sequencing and find several distinct microglial states during the early stages of remyelination that coalesce into a resolved state defined by the presence of myelin transcripts, a state also present in MS brains. We also observe a delay in the appearance of several microglial states with age, in concordance with delayed remyelination. This multi-faceted microglial response during efficient remyelination provides the basis of multi-faceted microglia-specific targets for future MS therapies.
Authors
- Kelly V. Lee
- Greg J. Duncan (ORCID: https://orcid.org/0000-0003-0203-9972)
- Abhisha M. Rathod (ORCID: https://orcid.org/0000-0002-4736-1992)
- Orsolya Farkas (ORCID: https://orcid.org/0000-0002-0828-7902)
- Sohrab B. Manesh
- Katherine Souter (ORCID: https://orcid.org/0000-0003-3136-263X)
- Marie‐Ève Tremblay (ORCID: https://orcid.org/0000-0003-2863-9626)
- Jason R. Plemel (ORCID: https://orcid.org/0000-0003-1385-1464)
- A. Pang (ORCID: https://orcid.org/0009-0008-8484-9787)
- Siva Reddy Challa (ORCID: https://orcid.org/0000-0003-0487-2757)
- Madelene F. S. Ho
- Brady P. Hammond (ORCID: https://orcid.org/0000-0001-7167-0683)
- Dhruvish Zaveri
- Geert J. Schenk (ORCID: https://orcid.org/0000-0002-9984-120X)
- Sameera Zia (ORCID: https://orcid.org/0000-0002-2956-0584)
- Wolfram Tetzlaff (ORCID: https://orcid.org/0000-0003-3462-1676)
- Timothy N. Friedman (ORCID: https://orcid.org/0000-0002-0058-5075)
- Andréia V. Faria (ORCID: https://orcid.org/0000-0002-1673-002X)
- B Szulc (ORCID: https://orcid.org/0000-0002-7782-9592)
- Aislinn D. Maguire (ORCID: https://orcid.org/0000-0003-4622-4598)
- Niels Meijns (ORCID: https://orcid.org/0000-0002-2561-0206)
- Rebecca K. John
- Fernando Gonzàlez Ibáñez (ORCID: https://orcid.org/0000-0003-3330-437X)
- Sharmistha P. Panda
- Anastassia Voronova (ORCID: https://orcid.org/0000-0001-7504-1905)
- Bradley J. Kerr (ORCID: https://orcid.org/0000-0002-0264-8316)
- Jeff Biernaskie (ORCID: https://orcid.org/0000-0002-0633-0698)
- Mena K. Burr
- Marianela E. Traetta (ORCID: https://orcid.org/0009-0007-1657-709X)
- Charbel S. Baaklini (ORCID: https://orcid.org/0000-0002-1075-0767)
- Sarthak Sinha (ORCID: https://orcid.org/0000-0002-0770-3150)
- E.G. Hahn
- Devhuti Vyas
- Luiz Tenorio
- Eva Dhupia
- Larry K. A. Afun
- Olivia R. La Caprara
Institutions
- University of British Columbia (CA)
- University of Alberta (CA)
- Oregon Health & Science University (US)
- University of Calgary (CA)
- University of Victoria (CA)
- Alberta Children's Hospital (CA)
- Amsterdam Neuroscience (NL)
- International Collaboration On Repair Discoveries (CA)
- Women and Children’s Health Research Institute (CA)
- Université Laval (CA)
- Hotchkiss Brain Institute (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-12
- DOI
- https://doi.org/10.1038/s41467-025-64906-w
- Citations
- 2
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.68
Funders
- U.S. Department of Defense
- National Multiple Sclerosis Society
- University of Alberta
- Multiple Sclerosis Society
- Alberta Innovates
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada