Targeting TrkB with a brain-derived neurotrophic factor mimetic promotes myelin repair in the brain

Jessica L. Fletcher, Rhiannon J. Wood, Jacqueline Nguyen, Eleanor M.L. Norman, Christine M.K. Jun, Alexa R. Prawdiuk, Melissa Biemond, Huynh T.H. Nguyen, Susan E. Northfield, Richard A. Hughes, David G. Gonsalvez, Junhua Xiao, Simon S. Murray

Research output: Contribution to journalArticleResearchpeer-review

31 Citations (Scopus)

Abstract

Methods to promote myelin regeneration in response to central myelin loss are essential to prevent the progression of clinical disability in demyelinating diseases. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to promote myelination during development via oligodendrocyte expressed TrkB receptors. Here, we use a structural mimetic of BDNF to promote myelin regeneration in a preclinical mouse model of central demyelination. In female mice, we show that selective targeting of TrkB with the BDNF-mimetic enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons, and myelin sheath thickness after a demyelinating insult. Treatment with exogenous BDNF exerted an attenuated effect, increasing myelin sheath thickness only. Further, following conditional deletion of TrkB from premyelinating oligodendrocytes, we show the effects of the BDNF-mimetic on oligodendrocyte differentiation and remyelination are lost, indicating these are dependent on oligodendrocyte expression of TrkB. Overall, these studies demonstrate that targeting oligodendrocyte TrkB promotes in vivo remyelination in the brain.

Original languageEnglish
Pages (from-to)7088-7099
Number of pages12
JournalJournal of Neuroscience
Volume38
Issue number32
DOIs
Publication statusPublished - 8 Aug 2018
Externally publishedYes

Keywords

  • BDNF
  • CNS
  • Neurotrophins
  • Oligodendrocytes
  • Remyelination
  • TrkB

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