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Exp. Mol. Med., 02 October 2023 | https://doi.org/10.1038/s12276-023-01073-2 Trametinib activates endogenous neurogenesis and recovers neuropathology in a model of Alzheimer’s disease

Mi-Yeon Kim ¹, Mi Jeong Kim ¹, Changyeob Lee ², Juwon Lee ², Sang Seong Kim ^3,9, Sungho Hong ⁴, Hyoung Tae Kim ^1,10, Jinsoo Seo ², Ki-Jun Yoon ^5,6,* and Sungho Han ^1,7,8,*

¹Neuroscience Research Center, Genuv Inc., Seoul 03175, Republic of Korea.
²Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea.
³College of Pharmacy, Hanyang University ERICA, Gyeonggi-do 15588, Republic of Korea.
⁴Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Okinawa 904-0495, Japan.
⁵Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
⁶KAIST Stem Cell Center, KAIST, Daejeon 34141, Republic of Korea.
⁷Head Office, Genuv Inc., Seoul 04520, Republic of Korea.
⁸Genuv US Subsidiary, Genuv Inc., Cambridge, USA.
⁹Present address: Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
¹⁰Present address: Shaperon Inc., Seoul 06373, Republic of Korea.

^*Corresponding authors: correspondence to Ki-Jun Yoon or Sungho Han

Abstract

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^INK4b 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.

논문정보

형식Research article
게재일2023년 10월 (BRIC 등록일 2023-10-04)
연구진국내(교신)+국외 연구진
분야 생명과학 > 신경생물학

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