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

Abstract

SummaryAimIt 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 (Aβ)‐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 Aβ‐mediated neurotoxicity have not yet been investigated.MethodsIn the present study, we evaluated the mechanisms by which linagliptin protects against Aβ‐induced impaired insulin signaling and cytotoxicity in cultured SK‐N‐MC human neuronal cells.ResultsOur results showed that Aβ impairs insulin signaling and causes cell death. However, linagliptin significantly protected against Aβ‐induced cytotoxicity, and prevented the activation of glycogen synthase kinase 3β (GSK3β) and tau hyperphosphorylation by restoring insulin downstream signaling. Furthermore, linagliptin alleviated Aβ‐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.ConclusionsTaken together, our findings suggest linagliptin can restore the impaired insulin signaling caused by Aβ in neuronal cells, suggesting DPP‐4 inhibitors may have therapeutic potential for reducing Aβ‐induced impairment of insulin signaling and neurotoxicity in AD pathogenesis.

Sitagliptin promotes mitochondrial biogenesis in human SH‐SY5Y cells by increasing the expression of PGC‐1α/NRF1/TFAM

“…Besides glycemic control, inhibition of DPP‐4 activity plays a critical role in neuroprotective effects under different pathological conditions. For example, the DPP‐4 inhibitor linagliptin plays an important role in inhibiting amyloid β (Aβ)‐induced neuronal cell apoptosis in an adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK) dependent pathway . Notably, sitagliptin has displayed its beneficial effects in neurological disorders by suppressing the expression of proinflammatory cytokines such as tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and cluster of differentiation 163 (CD‐163).…”

Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer’s Disease

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