1‐Deoxynojirimycin attenuates pathological markers of Alzheimer's disease in the in vitro model of neuronal insulin resistance

Abstract Insulin resistance, the hallmark of type 2 diabetes mellitus (T2DM), has emerged as a pathological feature in Alzheimer's disease (AD). Given the shared role of insulin resistance in T2DM and AD, repurposing peripheral insulin sensitizers is a promising strategy to preserve neuronal insulin sensitivity and prevent AD. 1‐Deoxynojirimycin (DNJ), a bioactive iminosugar, exhibited insulin‐sensitizing effects in metabolic tissues and was detected in brain tissue post‐oral intake. However, its impact on brain and neuronal insulin signaling has not been described. Here, we investigated the effect of DNJ treatment on insulin signaling and AD markers in insulin‐resistant human SK‐N‐SH neuroblastoma, a cellular model of neuronal insulin resistance. Our findings show that DNJ increased the expression of insulin signaling genes and the phosphorylation status of key molecules implicated in insulin resistance (Y1146‐pIRβ, S473‐pAKT, S9‐GSK3B) while also elevating the expression of glucose transporters Glut3 and Glut4 , resulting in higher glucose uptake upon insulin stimuli. DNJ appeared to mitigate the insulin resistance‐driven increase in phosphorylated tau and Aβ 1‐42 levels by promoting insulin‐induced phosphorylation of GSK3B (a major tau kinase) and enhancing mRNA expression of the insulin‐degrading enzyme (IDE) pivotal for insulin and Aβ clearance. Overall, our study unveils probable mechanisms underlying the potential benefits of DNJ for AD, wherein DNJ attenuates tau and amyloid pathologies by reversing neuronal insulin resistance. This provides a scientific basis for expanding the use of DNJ‐containing products for neuroprotective purposes and prompts further research into compounds with similar mechanisms of action.