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Trametinib activates endogenous neurogenesis and recovers neuropathology in a model of Alzheimer’s disease

Authors :
Ki-Jun Yoon
Mi-Yeon Kim
Mi Jeong Kim
Changyeob Lee
Hyoung Tae Kim
Jinsoo Seo
Sungho Han
Publication Year :
2022
Publisher :
Research Square Platform LLC, 2022.

Abstract

Enhancing adult neurogenesis in the brain has been suggested as a potential therapeutic for AD. We developed a screening platform ATRIVIEW® for molecules activating neuronal differentiation of adult mouse NSCs. Among FDA-approved drugs, the most potent hit was SNR1611 (trametinib), a selective MEK1/2 inhibitor. We found that trametinib increases the level of P15INK4b and Neurog2, suggesting a mechanism for how MEK1/2 inhibition induces neuronal differentiation. Oral administration of trametinib increased adult neurogenesis in the dentate gyrus and subventricular zone of the AD model mouse 5XFAD. Surprisingly, we also found that trametinib enhanced adult neurogenesis in the brain cortex. Consequently, trametinib rescued AD pathologies such as neuronal loss or cognitive impairment of 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........cd3eb183efb35addb78604e0758bfe01
Full Text :
https://doi.org/10.21203/rs.3.rs-2067756/v1