While Brain-derived Neurotrophic Factor (BDNF) has long been implicated in treating neurological diseases, recombinant BDNF protein has failed in multiple clinical trials. In addition to its unstable and adhesive nature, BDNF can activate p75NTR, a receptor mediating cellular functions opposite to those of TrkB. We have now identified TrkB agonistic antibodies (TrkB-agoAbs) with several properties superior to BDNF: They exhibit blood half-life of days instead of hours, diffuse centimeters in neural tissues instead millimeters, and bind and activate TrkB, but not p75NTR. In addition, TrkB-agoAbs elicit much longer TrkB activation, reduced TrkB internalization and less intracellular degradation, compared with BDNF. More importantly, some of these TrkB-agoAbs bind TrkB epitopes distinct from that by BDNF, and work cooperatively with endogenous BDNF. Unlike BDNF, the TrkB-agoAbs exhibit a half-life of days/weeks and diffused readily in nerve tissues. We tested one of TrkB-agoAbs further and showed that it enhanced motoneuron survival in the spinal-root avulsion model for motoneuron degeneration in vivo. Thus, TrkB-agoAbs are promising drug candidates for the treatment of neural injury.

Repeated failures of "Aβ-lowering" therapies call for new targets and therapeutic approaches for Alzheimer's disease (AD). We propose to treat AD by halting neuronal death and repairing synapses using a BDNF-based therapy. To overcome the poor druggability of BDNF, we have developed an agonistic antibody AS86 to mimic the function of BDNF, and evaluate its therapeutic potential for AD. Method: Biochemical, electrophysiological and behavioral techniques were used to investigate the effects of AS86 in vitro and in vivo. Results: AS86 specifically activated the BDNF receptor TrkB and its downstream signaling, without affecting its other receptor p75NTR. It promoted neurite outgrowth, enhanced spine growth and prevented Aβ-induced cell death in cultured neurons, and facilitated Long-Term Potentiation (LTP) in hippocampal slices. A single-dose tail-vein injection of AS86 activated TrkB signaling in the brain, with a half-life of 6 days in the blood and brain. Bi-weekly peripheral administration of AS86 rescued the deficits in object-recognition memory in the APP/PS1 mouse model. AS86 also reversed spatial memory deficits in the 11-month, but not 14-month old AD mouse model. Conclusion: These results demonstrate the potential of AS86 in AD therapy, suggesting that neuronal and/or synaptic repair as an alternative therapeutic strategy for AD.