Alzheimer‘s disease (AD) is a neurodegenerative disorder characterized by deposition of Aβ. Our therapeutic strategy for AD is to regenerate neural circuits in the brain to recover memory function. We previously found diosgenin as a candidate drug for regenerating axons in the brain and improving memory impairment in AD model (5XFAD) mouse. In addition, diosgenin-driven axonal regeneration is mediated by changes in expression levels of several proteins (e.g. SPARC, Galectin-1) in neurons. In this study, we aimed to explore key candidate molecules that regulate the expression of these axonal regeneration-related proteins and clarify their contributions to axonal regeneration and memory recovery.
RNA-seq analysis revealed that 7-day treatment of diosgenin (1 μM) to hippocampal neurons (ddY mice, P7) drastically upregulated the expression of Rn7sk, one of the well-known transcription factors. Overexpression of Rn7sk significantly promoted axonal growth and upregulated the expression of SPARC in primary cultured hippocampal neurons, and also recovered memory deficits in 5XFAD mice. This study suggests that Rn7sk may be a responsible molecule for diosgenin-induced axonal regeneration, which proposes a novel therapeutic target for AD treatment.