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

View ORCID ProfileJessica L Fletcher, Rhiannon J Wood, Jacqueline Nguyen, Eleanor ML Norman, Christine MK Jun, Alexa R Prawdiuk, Melissa Biemond, Huynh TH Nguyen, Susan E Northfield, Richard A Hughes, David G Gonsalvez, Junhua Xiao, Simon S Murray
doi: https://doi.org/10.1101/268300
Jessica L Fletcher
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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  • ORCID record for Jessica L Fletcher
Rhiannon J Wood
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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Jacqueline Nguyen
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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Eleanor ML Norman
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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Christine MK Jun
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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Alexa R Prawdiuk
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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Melissa Biemond
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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Huynh TH Nguyen
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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Susan E Northfield
bDepartment of Pharmacology and Therapeutics School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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Richard A Hughes
bDepartment of Pharmacology and Therapeutics School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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David G Gonsalvez
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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Junhua Xiao
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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Simon S Murray
aDepartment of Anatomy and Neuroscience, School of Biomedical Science, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3052, VIC, AUSTRALIA
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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. 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 pre-myelinating 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.

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Posted February 20, 2018.
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Targeting TrkB with a brain-derived neurotrophic factor mimetic promotes myelin repair in the brain
Jessica L Fletcher, Rhiannon J Wood, Jacqueline Nguyen, Eleanor ML Norman, Christine MK Jun, Alexa R Prawdiuk, Melissa Biemond, Huynh TH Nguyen, Susan E Northfield, Richard A Hughes, David G Gonsalvez, Junhua Xiao, Simon S Murray
bioRxiv 268300; doi: https://doi.org/10.1101/268300
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Targeting TrkB with a brain-derived neurotrophic factor mimetic promotes myelin repair in the brain
Jessica L Fletcher, Rhiannon J Wood, Jacqueline Nguyen, Eleanor ML Norman, Christine MK Jun, Alexa R Prawdiuk, Melissa Biemond, Huynh TH Nguyen, Susan E Northfield, Richard A Hughes, David G Gonsalvez, Junhua Xiao, Simon S Murray
bioRxiv 268300; doi: https://doi.org/10.1101/268300

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