Neuroscience Research Center, Genuv Inc., Seoul, 03175, Republic of Korea.
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, Republic of Korea.
Exp Mol Med. 2023 Oct;55(10):2177-2189. doi: 10.1038/s12276-023-01073-2. Epub 2023 Oct 2.
Enhancing adult neurogenesis in the brain has been suggested as a potential therapeutic strategy for AD. We developed a screening platform, ATRIVIEW, for molecules that activate neuronal differentiation of adult mouse NSCs. The most potent hit from an FDA-approved drug library was SNR1611 (trametinib), a selective MEK1/2 inhibitor. We found that trametinib increases the levels of P15 and Neurog2, suggesting a mechanism by which MEK1/2 inhibition induces neuronal differentiation. Oral administration of trametinib increased adult neurogenesis in the dentate gyrus and subventricular zone of the 5XFAD AD mouse model. Surprisingly, we also found that trametinib enhanced adult neurogenesis in the cortex. Consequently, trametinib rescued AD pathologies such as neuronal loss and cognitive impairment in 5XFAD mice. Finally, trametinib induced neurogenic differentiation of NSCs derived from AD patient iPSCs, which suggests its potential therapeutic application. Altogether, we suggest that restoration of endogenous adult neurogenesis by trametinib may be a promising therapeutic approach to AD.
增强大脑中的成人神经发生已被认为是 AD 的一种潜在治疗策略。我们开发了一种筛选平台 ATRIVIEW，用于筛选能激活成年小鼠 NSCs 神经元分化的分子。从 FDA 批准药物库中筛选出的最有效化合物是 SNR1611（曲美替尼），一种选择性 MEK1/2 抑制剂。我们发现曲美替尼增加了 P15 和 Neurog2 的水平，提示 MEK1/2 抑制诱导神经元分化的机制。曲美替尼的口服给药可增加 5XFAD AD 小鼠模型齿状回和侧脑室下区的成年神经发生。令人惊讶的是，我们还发现曲美替尼增强了大脑皮层的成年神经发生。因此，曲美替尼可挽救 5XFAD 小鼠的 AD 病理，如神经元丢失和认知障碍。最后，曲美替尼诱导 AD 患者 iPSC 来源的 NSCs 的神经发生分化，提示其具有潜在的治疗应用。总之，我们认为曲美替尼恢复内源性成年神经发生可能是 AD 的一种有前途的治疗方法。
