TY - JOUR T1 - Targeting TrkB with a brain-derived neurotrophic factor mimetic promotes myelin repair in the brain JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.0487-18.2018 SP - 0487-18 AU - Jessica L Fletcher AU - Rhiannon J Wood AU - Jacqueline Nguyen AU - Eleanor ML Norman AU - Christine MK Jun AU - Alexa R Prawdiuk AU - Melissa Biemond AU - Huynh TH Nguyen AU - Susan E Northfield AU - Richard A Hughes AU - David G Gonsalvez AU - Junhua Xiao AU - Simon S Murray Y1 - 2018/07/05 UR - http://www.jneurosci.org/content/early/2018/07/05/JNEUROSCI.0487-18.2018.abstract N2 - 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 axonsnd 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.SIGNIFICANCE STATEMENTNovel strategies to promote myelin regeneration are required to prevent progressive neurodegeneration and clinical disability in patients with central demyelinating disease. Here, we test if 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. ER -