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Exendin-4 protects Aβ(1-42) oligomer-induced PC12 cell apoptosis
Chen Qiu1, Yan-Ping Wang2, Xiao-Dong Pan3
1Fujian 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.
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.
Insights
Glucagon-like peptide-1 (GLP-1) analogue exendin-4 (Ex-4) protects against amyloid-beta oligomer (AβO)-induced neuronal apoptosis. Ex-4 reverses AβO-induced impairment of the Akt/CREB survival pathway, suggesting its potential for Alzheimer
Area of Science:
- Neuroscience
- Endocrinology
- Molecular Biology
Background:
- Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD).
- Glucagon-like peptide-1 (GLP-1) analogs demonstrate neuroprotective effects in neurodegenerative diseases.
- The precise mechanism of GLP-1's neuroprotection remains under investigation.
Purpose of the Study:
- To investigate the neuroprotective effect of exendin-4 (Ex-4), a GLP-1 receptor agonist, against amyloid-beta(1-42) oligomer (AβO)-induced apoptosis.
- To elucidate the underlying molecular mechanisms of Ex-4's action in a PC12 neuronal cell model.
Main Methods:
- PC12 neuronal cells were exposed to AβOs to induce apoptosis.
- Cell viability was assessed using MTT assays.
- Apoptosis was quantified via DAPI and Annexin-V/PI staining.
- Protein expression levels of caspase-3, Bcl-2, Akt, and CREB were analyzed.
- Phosphorylation of Akt and CREB was measured to assess pathway activation.
Main Results:
- AβOs significantly reduced PC12 cell viability and induced apoptosis in a dose- and time-dependent manner.
- Ex-4 pre-treatment attenuated AβO-induced apoptosis and improved cell viability.
- AβOs decreased the expression of anti-apoptotic protein Bcl-2 and the phosphorylation of Akt and CREB.
- Ex-4 pre-treatment upregulated Bcl-2 expression and restored Akt and CREB phosphorylation.
Conclusions:
- Exendin-4 (Ex-4) exhibits significant neuroprotective effects against AβO-induced apoptosis in PC12 cells.
- Ex-4 exerts its neuroprotection by reversing AβO-induced impairment of the Akt/CREB neuronal survival signaling pathway.
- Ex-4 represents a potential therapeutic strategy for mitigating AβO-induced neurotoxicity in Alzheimer's disease, particularly in diabetic patients.
