Journal Article

Age-impaired remyelination is associated with dysregulated microglial transitions

Farkas, Olivia, Tenorio, Luiz, La Caprara, Olivia R., Szulc, Bożena, Baaklini, Charbel S., John, Rebecca K., González Ibáñez, Fernando, Dhupia, Eva, Vyas, Diya, Hahn, Eugene, Burr, Mena K., Schenk, Geert, Sinha, Sarthak, Duncan, Gregory J., Ho, Madelene F. S., Maguire, Aislinn D., Hammond, Brady P., Souter, Katherine M., Traetta, Marianela E., Friedman, Timothy N., Manesh, Sohrab B., Challa, Sowmya, Lee, Kelly V., Kerr, Bradley J., Tremblay, Marie-Eve, Zaveri, Dhruvish, Rathod, Abhisha M., Voronova, Anastassia, Pang, Arina, Plemel, Jason R., Zia, Sameera, Meijns, Niels, Afun, Larry K. A., Panda, Sharmistha, Faria, Andre O., Biernaskie, Jeff, Tetzlaff, Wolfram

2025

Overview

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. Microglial states throughout remyelination are incompletely understood. Here, the authors show that microglia form several states during the early stages of remyelination that coalesce into a partially resolved state that is dysregulated with age.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/31 / 13/51 / 14/19 / 14/28 / 14/32 / 49/91 / 631/378/2596/1953 / 631/378/2606/1666 / 631/378/371 / Age / Aging - pathology / Animals / Brain - metabolism / Brain - pathology / Demyelinating Diseases - pathology / Demyelination / Disease Models, Animal / Female / Gene expression / Gene sequencing / Humanities and Social Sciences / Humans / Lysophosphatidylcholines - toxicity / Male / Mice / Mice, Inbred C57BL / Microglia / Microglia - metabolism / Microglia - pathology / Middle age / multidisciplinary / Multiple sclerosis / Multiple Sclerosis - genetics / Multiple Sclerosis - metabolism / Multiple Sclerosis - pathology / Myelin / Myelin Sheath - metabolism / Myelin Sheath - pathology / Myelination / Neurodegeneration / Remyelination - genetics / Remyelination - physiology / Science / Science (multidisciplinary) / Single-Cell Analysis / Spinal cord / Transcription factors / Variance analysis