title: Exendin-4 protects Aβ(1-42) oligomer-induced PC12 cell apoptosis.
abstract: BACKGROUND
  Type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer's disease. Most recently, GLP-1 analogs have been shown to have a significant neuroprotective role in several neurodegenerative diseases. However, few are known on its potential mechanism.
  
  
  OBJECTIVE
  In this study, we report the effect of exendin-4 (Ex-4), a GLP-1 receptor agonist, on amyloid-β(1-42) peptide oligomer-induced apoptosis in a PC12 neuronal cell model.
  
  
  METHODS
  MTT, DAPI and Annexin-V/PI assays revealed that the viability of PC12 cells decreased in a dose- and time-dependent manner after exposure to amyloid-β(1-42) oligomers. This apoptotic effect could be attenuated by Ex-4 (100-300 nM) pre-treatment, compared with the PC12 cells treated with amyloid-β(1-42) oligomers alone. Moreover, treatment with amyloid-β(1-42) oligomers (10 μM) resulted in a decrease in active- and pro-caspase-3 expression, as well as in Bcl-2 protein expression; suggesting that amyloid-β(1-42) oligomers impaired neuronal cells via the apoptosis signaling pathway. A further study of this mechanism revealed that amyloid-β oligomers (AβOs) decreased the phosphorylation of Akt and CREB. As expected, pre-treatment with Ex-4 (300 nM) increased the expression of anti-apoptotic protein Bcl-2 and reduced active caspase-3 expression levels. In addition, Ex-4 upregulated the phosphorylation levels of Akt and CREB.
  
  
  CONCLUSIONS
  These findings indicate that GLP-1 analogue Ex-4 has a neuroprotective effect against AβO-induced PC12 cell apoptosis through reversing the impairment of the neuronal survival signaling pathway. This strongly suggests that Ex-4 is a potential therapeutic option for ameliorating AβO-induced neurotoxicity in the clinical application of Ex-4 for AD treatment, particularly when associated with diabetes.
authors.affiliation: Fujian Institute of Endocrinology, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China; Department of Endocrinology, People's Hospital Affiliated to Fujian University of Traditional Chinese MedicineFuzhou 350004, Fujian, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Fujian Institute of Endocrinology, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China; Department of Endocrinology, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China; Department of Geriatrics, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Department of Neurology, Fujian Medical University Union Hospital Fuzhou 350001, Fujian, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Pan
authors.affiliation: Fujian Institute of Endocrinology, Fujian Medical University Union Hospital Fuzhou 350001, Fujian, China.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Liu
authors.affiliation: College of Pharmacy, Fujian Medical University Fuzhou 350108, Fujian, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Fujian Institute of Endocrinology, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China; Institute of Geriatric Health Science, Fujian Medical UniversityFuzhou 350001, Fujian, China.
authors.forename: Li-Bin
authors.initials: LB
authors.lastname: Liu
keywords: Exendin-4; amyloid-β(1-42) oligomers; apoptosis; neuronal cells; neuronal survival signaling