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./nMethod: Biochemical, electrophysiological and behavioral techniques were used to investigate the effects of AS86 in vitro and in vivo./nResults: AS86 specifically activated the BDNF receptor TrkB and its downstream signaling, without affecting its other receptor p75^NTR. 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./nConclusion: These results demonstrate the potential of AS86 in AD therapy, suggesting that neuronal and/or synaptic repair as an alternative therapeutic strategy for AD.

中文翻译：

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TrkB 激动性抗体对阿尔茨海默病的治疗潜力。


“降低 Aβ”疗法屡屡失败，需要针对阿尔茨海默病 (AD) 寻找新的靶点和治疗方法。我们建议通过使用基于 BDNF 的疗法阻止神经元死亡和修复突触来治疗 AD。为了克服 BDNF 的成药性差的问题，我们开发了一种激动性抗体 AS86 来模拟 BDNF 的功能，并评估其治疗 AD 的潜力。/n方法：采用生化、电生理和行为技术研究 AS86 的体外作用/ n结果： AS86 特异性激活 BDNF 受体 TrkB 及其下游信号传导，而不影响其其他受体 p75 ^NTR 。它促进神经突生长，增强脊柱生长，防止培养神经元中 Aβ 诱导的细胞死亡，并促进海马切片中的长时程增强 (LTP)。单剂量尾静脉注射 AS86 可激活大脑中的 TrkB 信号传导，在血液和大脑中的半衰期为 6 天。每两周外周注射 AS86 可以挽救 APP/PS1 小鼠模型的物体识别记忆缺陷。 AS86 还逆转了 11 个月大的 AD 小鼠模型的空间记忆缺陷，但不能逆转 14 个月大的 AD 小鼠模型。/n结论：这些结果证明了 AS86 在 AD 治疗中的潜力，表明神经元和/或突触修复作为替代治疗策略对于AD。