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

Citation

Fletcher, JL and Wood, RJ and Nguyen, J and Norman, EML and Jun, CMK and Prawdiuk, AR and Biemond, M and Nguyen, HTH and Northfield, SE and Hughes, RA and Gonsalvez, DG and Xiao, J and Murray, SS, Targeting TrkB with a brain-derived neurotrophic factor mimetic promotes myelin repair in the brain, Journal of Neuroscience, 38, (32) pp. 7088 -7099. ISSN 0270-6474 (2018) [Refereed Article]

Copyright Statement

Copyright 2018 the authors

DOI: doi:10.1523/JNEUROSCI.0487-18.2018

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.

SIGNIFICANCE STATEMENT: Novel strategies to promote myelin regeneration are required to prevent progressive neurodegeneration and clinical disability in patients with central demyelinating disease. Here, we test whether selectively targeting the TrkB receptor on the myelin-producing oligodendrocytes, can promote remyelination in the brain. Using a structural mimetic of its native ligand, BDNF, we show that stimulation of TrkB enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons and thickness of the myelin sheath following a demyelinating insult. Further, we show that these effects are dependent on the phosphorylation of oligodendrocyte expressed TrkB receptors in vivo Overall, we demonstrate that selective targeting of TrkB has therapeutic potential to promote remyelination in the brain.

Item Details

Item Type:Refereed Article
Keywords:oligodendrocyte, myelin, BDNF, multiple sclerosis, demyelinating disease, animal models
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biomedical and clinical sciences
UTAS Author:Fletcher, JL (Dr Jessica Fletcher)
ID Code:147219
Year Published:2018
Web of Science® Times Cited:34
Deposited By:Menzies Institute for Medical Research
Deposited On:2021-10-19
Last Modified:2021-11-03
Downloads:0

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