PMID- 29976621 OWN - NLM STAT- MEDLINE DCOM- 20191112 LR - 20200306 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 38 IP - 32 DP - 2018 Aug 8 TI - Targeting TrkB with a Brain-Derived Neurotrophic Factor Mimetic Promotes Myelin Repair in the Brain. PG - 7088-7099 LID - 10.1523/JNEUROSCI.0487-18.2018 [doi] AB - 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. CI - Copyright (c) 2018 the authors 0270-6474/18/387088-12$15.00/0. FAU - Fletcher, Jessica L AU - Fletcher JL AUID- ORCID: 0000-0003-2009-0798 AD - Departments of Anatomy and Neuroscience, and jessica.fletcher@unimelb.edu.au ssmurray@unimelb.edu.au. FAU - Wood, Rhiannon J AU - Wood RJ AD - Departments of Anatomy and Neuroscience, and. FAU - Nguyen, Jacqueline AU - Nguyen J AD - Departments of Anatomy and Neuroscience, and. FAU - Norman, Eleanor M L AU - Norman EML AUID- ORCID: 0000-0003-1227-9988 AD - Departments of Anatomy and Neuroscience, and. FAU - Jun, Christine M K AU - Jun CMK AD - Departments of Anatomy and Neuroscience, and. FAU - Prawdiuk, Alexa R AU - Prawdiuk AR AD - Departments of Anatomy and Neuroscience, and. FAU - Biemond, Melissa AU - Biemond M AD - Departments of Anatomy and Neuroscience, and. FAU - Nguyen, Huynh T H AU - Nguyen HTH AD - Departments of Anatomy and Neuroscience, and. FAU - Northfield, Susan E AU - Northfield SE AD - Pharmacology and Therapeutics, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, Victoria, Australia. FAU - Hughes, Richard A AU - Hughes RA AD - Pharmacology and Therapeutics, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, Victoria, Australia. FAU - Gonsalvez, David G AU - Gonsalvez DG AD - Departments of Anatomy and Neuroscience, and. FAU - Xiao, Junhua AU - Xiao J AUID- ORCID: 0000-0002-4320-2855 AD - Departments of Anatomy and Neuroscience, and. FAU - Murray, Simon S AU - Murray SS AUID- ORCID: 0000-0001-6671-192X AD - Departments of Anatomy and Neuroscience, and jessica.fletcher@unimelb.edu.au ssmurray@unimelb.edu.au. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180705 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Membrane Glycoproteins) RN - 0 (Myelin Basic Protein) RN - 0 (Peptides, Cyclic) RN - 0 (tricyclic-dimeric-peptide-6) RN - 5N16U7E0AO (Cuprizone) RN - EC 2.7.10.1 (Ntrk2 protein, mouse) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) SB - IM MH - Animals MH - Brain/*drug effects/metabolism/pathology MH - Brain-Derived Neurotrophic Factor/pharmacology/*therapeutic use MH - Cell Division/drug effects MH - Corpus Callosum/metabolism/pathology MH - Cuprizone/toxicity MH - Demyelinating Diseases/chemically induced/*drug therapy/pathology MH - Female MH - Infusion Pumps, Implantable MH - Infusions, Intraventricular MH - Male MH - Membrane Glycoproteins/*agonists/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - *Molecular Targeted Therapy MH - Myelin Basic Protein/biosynthesis MH - Myelin Sheath/*metabolism MH - Neural Stem Cells/drug effects MH - Oligodendroglia/*drug effects MH - Peptides, Cyclic/pharmacology/therapeutic use MH - Phosphorylation MH - Protein Processing, Post-Translational/drug effects MH - Protein-Tyrosine Kinases/metabolism MH - Remyelination/*drug effects MH - Specific Pathogen-Free Organisms PMC - PMC6596092 OTO - NOTNLM OT - BDNF OT - CNS OT - TrkB OT - neurotrophins OT - oligodendrocytes OT - remyelination EDAT- 2018/07/07 06:00 MHDA- 2019/11/13 06:00 PMCR- 2019/02/08 CRDT- 2018/07/07 06:00 PHST- 2018/02/20 00:00 [received] PHST- 2018/06/01 00:00 [revised] PHST- 2018/06/25 00:00 [accepted] PHST- 2018/07/07 06:00 [pubmed] PHST- 2019/11/13 06:00 [medline] PHST- 2018/07/07 06:00 [entrez] PHST- 2019/02/08 00:00 [pmc-release] AID - JNEUROSCI.0487-18.2018 [pii] AID - 0487-18 [pii] AID - 10.1523/JNEUROSCI.0487-18.2018 [doi] PST - ppublish SO - J Neurosci. 2018 Aug 8;38(32):7088-7099. doi: 10.1523/JNEUROSCI.0487-18.2018. Epub 2018 Jul 5.