title: DPP-4 Inhibitor Linagliptin Attenuates Aβ-induced Cytotoxicity through Activation of AMPK in Neuronal Cells.
abstract: OBJECTIVE
  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 (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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  Taken 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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.|Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Edy
authors.initials: E
authors.lastname: Kornelius
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Hsiu-Han
authors.initials: HH
authors.lastname: Chang
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Hsin-Hua
authors.initials: HH
authors.lastname: Li
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Wen-Nung
authors.initials: WN
authors.lastname: Huang
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.|Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yi-Sun
authors.initials: YS
authors.lastname: Yang
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.|Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Lu
authors.affiliation: Division of Basic Medical Science, Hungkuang University, Taichung, Taiwan.
authors.forename: Chiung-Huei
authors.initials: CH
authors.lastname: Peng
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.|Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chien-Ning
authors.initials: CN
authors.lastname: Huang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000503:physiopathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D000069476:Linagliptin / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D016229:Amyloid beta-Peptides; D002867:Chromones; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D009025:Morpholines; D010446:Peptide Fragments; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; C075222:amyloid beta-protein (1-42); C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000069476:Linagliptin; D007334:Insulin-Like Growth Factor I; D052216:Glucagon-Like Peptide 1; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: AMP-activated protein kinase; Alzheimer's disease; Amyloid-β; Linagliptin; Sirtuin 1