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Aim It is now clear that insulin signaling has important roles in regulation of neuronal functions in the brain. Dysregulation of brain insulin signaling has been linked to neurodegenerative disease, particularly Alzheimer's disease ( AD). In this regard, there is evidence that improvement of neuronal insulin signaling has neuroprotective activity against amyloid β (A β)-induced neurotoxicity for patients with AD. Linagliptin is an inhibitor of dipeptidylpeptidase-4 ( DPP-4), which improves impaired insulin secretion and insulin downstream signaling in the in peripheral tissues. However, whether the protective effects of linagliptin involved in A β-mediated neurotoxicity have not yet been investigated. Methods In the present study, we evaluated the mechanisms by which linagliptin protects against A β-induced impaired insulin signaling and cytotoxicity in cultured SK-N- MC human neuronal cells. Results Our results showed that A β impairs insulin signaling and causes cell death. However, linagliptin significantly protected against A β-induced cytotoxicity, and prevented the activation of glycogen synthase kinase 3 β ( GSK3 β) and tau hyperphosphorylation by restoring insulin downstream signaling. Furthermore, linagliptin alleviated A β-induced mitochondrial dysfunction and intracellular ROS generation, which may be due to the activation of 5′ AMP-activated protein kinase ( AMPK)-Sirt1 signaling. This upregulation of Sirt1 expression was also observed in diabetic patients with AD coadministration of linagliptin. Conclusions Taken together, our findings suggest linagliptin can restore the impaired insulin signaling caused by A β in neuronal cells, suggesting DPP-4 inhibitors may have therapeutic potential for reducing A β-induced impairment of insulin signaling and neurotoxicity in AD pathogenesis. [ABSTRACT FROM AUTHOR]