Thirty years of BDNF study in central myelination: From biology to therapy

Being the highest expressed neurotrophin in the mammalian brain, the brain-derived neurotrophic factor (BDNF) is essential to neural development and plasticity in both health and diseases. Following the discovery of BDNF by Yves-Alain Barde in 1982, the main feature of BDNF's activity in myelination was first described by Cellerino et al. in 1997. Since then, genetic manipulation of the BDNF-encoding gene and its receptors in murine models has revealed the contribution of BDNF to the myelinating process in the central nervous system (CNS). The series of BDNF or receptor mouse mutants as well as the BDNF polymorphism in humans have provided new insights into the roles that BDNF signaling plays in myelination in a complex manner. 2024 marks the 30th year of BDNF's research in myelination. Here, we share our perspective on the 30-year history of BDNF in the field of CNS myelination from phenotyping to therapeutic development, focusing on genetic evidence regarding the mechanism by which BDNF regulates myelin formation and repair in the CNS. This review also discusses the current hypotheses of BDNF's action on CNS myelination: axonal- and oligodendroglial-driven mechanisms, which may be ultimately activity-dependent. Last, this review raises the challenges and opportunities of developing BDNF-based therapies for neurodegenerative diseases, opening unanswered questions for future investigation.