Therapeutic potential of a TrkB agonistic antibody for Alzheimer's disease.

ABSTRACT: Repeated failures of "A?-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 A?-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.

SUBMITTER: Wang S 

PROVIDER: S-EPMC7295064 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature