Can drug-like mimetics of BDNF promote remyelination after injury?
We have found that BDNF activates distinct receptors to regulate myelination: BDNF activates the receptor tyrosine kinase TrkB to promote CNS myelination, but activates the p75NTR neurotrophin receptor to promote PNS myelination. This project aims to investigate whether we can develop methods to selectively and independently activate either TrkB or p75NTR, and use these to promote myelin repair in vivo. To this end, we have developed two novel low molecular weight peptides of BDNF designed to selectively activate its receptors:
TDP6 – Tricyclic dimeric peptide 6 (TDP6) is a small multicyclic peptide that structurally mimics the region of BDNF that binds TrkB. We have confirmed that TDP6 acts as a TrkB agonist and promotes oligodendrocyte myelination in vitro. This project will investigate whether TDP6 can also promote myelin repair in an animal model of CNS demyelination.
cyclo-dPAKKR – is a cyclic pentapetide that structurally mimics the region of BDNF that binds p75NTR. We have confirmed that cyclo-dPAKKR significantly promotes Schwann cell myelination in vitro and peripheral myelination in vivo. This project will investigate whether cyclo-dPAKKR can also promote myelin repair in an animal model of PNS demyelination.
We are interested in examining whether selectively targeting BDNF receptors through these peptides is a strategy that can promote myelin repair.
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