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 (R), 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 P15INK4b 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. "Trametinib, a MEK1/2 inhibitor, promotes adult neurogenesis in an Alzheimer's disease mouse model and human iPSC-derived neural stem cells." Researchers have discovered that trametinib, a MEK1/2 inhibitor, can enhance adult neurogenesis and replenish neurons in brain areas where neurodegeneration most affects Alzheimer's disease (AD). The study found that trametinib induced neuronal differentiation of adult neural stem cells and restored impaired neurogenesis in the hippocampus and subventricular zone of the AD model mice, in addition to inducing adult cortical neurogenesis. It also demonstrated trametinib's potential for inducing neurogenic differentiation in AD patient-induced pluripotent stem cells (iPSCs)-derived NSCs. These findings suggest that trametinib could be a promising therapeutic approach for treating AD and other neurodegenerative diseases by promoting adult neurogenesis.