DPP-4 Inhibitor Linagliptin Attenuates Aβ-induced Cytotoxicity through Activation of AMPK in Neuronal Cells

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 neurode-generative disease, particularly Alzheimer's disease (AD). In this regard, there is evidence that improvement of neuronal insulin signaling has neuroprotective activity against amyloid beta (A beta)-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 beta-mediated neurotoxicity have not yet been investigated. Methods: In the present study, we evaluated the mechanisms by which linagliptin protects against Ab-induced impaired insulin signaling and cytotoxicity in cultured SK-N-MC human neuronal cells. Results: Our results showed that Ab impairs insulin signaling and causes cell death. However, linagliptin significantly protected against A beta-induced cytotoxicity, and prevented the activation of glycogen synthase kinase 3 beta (GSK3 beta) and tau hyper-phosphorylation by restoring insulin downstream signaling. Furthermore, linagliptin alleviated A beta-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 Ab in neuronal cells, suggesting DPP-4 inhibitors may have therapeutic potential for reducing A beta-induced impairment of insulin signaling and neurotoxicity in AD pathogenesis.