School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Joint Graduate Program of Peking-Tsinghua-NIBS, Tsinghua University, Beijing, 100084, China.
Beijing Tiantan Hospital, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100070, China.
Nat Commun. 2022 Feb 17;13(1):914. doi: 10.1038/s41467-022-28611-2.
Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. Here we show that intravenous injection of Ab4B19, an agonistic antibody for the BDNF receptor TrkB, penetrates into ovarian follicles, activates TrkB signaling, and promotes ovary development. In both natural aging and cyclophosphamide-induced POF models, treatment with Ab4B19 completely reverses the reduction of pre-antral and antral follicles, and normalizes gonadal hormone. Ab4B19 also attenuates gonadotoxicity and inhibits apoptosis in cyclophosphamide-induced POF ovaries. Further, treatment with Ab4B19, but not BDNF, restores the number and quality of oocytes and enhances fertility. In human, BDNF levels are high in granulosa cells and TrkB levels increase in oocytes as they mature. Moreover, BDNF expression is down-regulated in follicles of aged women, and Ab4B19 activates TrkB signaling in human ovary tissue ex vivo. These results identify TrkB as a potential target for POF with differentiated mechanisms, and confirms superiority of TrkB activating antibody over BDNF as therapeutic agents.
卵巢早衰（POF）是女性不孕的主要原因，目前尚无有效的治疗方法。本文中我们发现，BDNF 受体 TrkB 的激动性抗体 Ab4B19 经静脉注射后可穿透卵巢卵泡，激活 TrkB 信号通路，从而促进卵巢发育。在自然衰老和环磷酰胺诱导的 POF 模型中，Ab4B19 治疗可完全逆转窦前卵泡和窦卵泡数量减少，并使性腺激素恢复正常。Ab4B19 还可减轻环磷酰胺诱导的 POF 卵巢的性腺毒性并抑制细胞凋亡。此外，Ab4B19 治疗而非 BDNF 治疗可恢复卵母细胞数量和质量，并提高生育能力。在人类中，BDNF 在颗粒细胞中的水平较高，且 TrkB 水平在卵母细胞成熟过程中增加。此外，衰老女性的卵泡中 BDNF 表达下调，Ab4B19 可在人卵巢组织离体实验中激活 TrkB 信号通路。这些结果表明，TrkB 是一种具有不同机制的潜在 POF 治疗靶点，证实了 TrkB 激活性抗体优于 BDNF 作为治疗药物的优势。
