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

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

SUBMITTER: Kim MY 

PROVIDER: S-EPMC10618442 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature