The ApoA-I mimetic peptide 5A enhances remyelination by promoting clearance and degradation of myelin debris

  • Cell Rep. 2022 Nov 8;41(6):111591. doi: 10.1016/j.celrep.2022.111591.
Sam Vanherle  1 ,  Winde Jorissen  1 ,  Tess Dierckx  1 ,  Melanie Loix  1 ,  Elien Grajchen  1 ,  Fleur Mingneau  1 ,  Jeroen Guns  1 ,  Pascal Gervois  2 ,  Ivo Lambrichts  2 ,  Jonas Dehairs  3 ,  Johannes V Swinnen  3 ,  Monique T Mulder  4 ,  Alan T Remaley  5 ,  Mansour Haidar  1 ,  Jerome J A Hendriks  1 ,  Jeroen J F Bogie  6
Affiliations
  • 1. Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; University MS Center Hasselt, 3900 Pelt, Belgium.
  • 2. Department of Cardio and Organs Systems, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium.
  • 3. Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven Cancer Institute, University of Leuven, 3000 Leuven, Belgium.
  • 4. Department of Internal Medicine, Erasmus University Medical Center, 3015 Rotterdam, the Netherlands.
  • 5. Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 6. Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; University MS Center Hasselt, 3900 Pelt, Belgium. Electronic address: [email protected].
PMID: 36351388 DOI: 10.1016/j.celrep.2022.111591
Abstract

The progressive nature of demyelinating diseases lies in the inability of the central nervous system (CNS) to induce proper remyelination. Recently, we and Others demonstrated that a dysregulated innate immune response partially underlies failure of CNS remyelination. Extensive accumulation of myelin-derived lipids and an inability to process these lipids was found to induce a disease-promoting phagocyte phenotype. Hence, restoring the ability of these phagocytes to metabolize and efflux myelin-derived lipids represents a promising strategy to promote remyelination. Here, we show that ApoA-I mimetic peptide 5A, a molecule well known to promote activity of the lipid efflux transporter ABCA1, markedly enhances remyelination. Mechanistically, we find that the repair-inducing properties of 5A are attributable to increased clearance and metabolism of remyelination-inhibiting myelin debris via the fatty acid translocase protein CD36, which is transcriptionally controlled by the ABCA1-JAK2-STAT3 signaling pathway. Altogether, our findings indicate that 5A promotes remyelination by stimulating clearance and degradation of myelin debris.

Keywords
ApoA-I mimetic peptide 5A; CP: Neuroscience; lipid droplet degradation; myelin debris clearance; phagocyte; remyelination.
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