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PPARα Activation Attenuates Amyloid-β-Dependent Neurodegeneration by Modulating Endo G and AIF Translocation

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Abstract

The accumulation of a large amount of amyloid-β (Aβ42) in brain neurons is one of the debilitating characteristics of Alzheimer’s disease. In this study, we determined the effects of peroxisome proliferator-activated receptor alpha (PPARα) activation on neuronal degeneration using a model of Aβ42-induced cytotoxicity. We found that 0.5 μM Aβ42 induced DNA damage and apoptosis in NT2N cells after 6 h of treatment. Co-treatment of Aβ42-treated cells with Wy14643, a PPARα ligand, significantly increased cell viability after 24 h compared with cells treated with Aβ42 alone. There were no differences in the protein levels of caspase-3, Bcl-2/Bax or p53 between cells treated with Aβ42 alone and those treated with both Aβ42 and Wy14643. However, the addition of Wy14643 significantly suppressed the Aβ42-induced upregulation of Endo G and AIF protein levels. Immunohistochemical analyses further demonstrated that Wy14643 reduced the expression of Endo G and AIF translocated from the cytoplasm into the nucleus, which occurred concomitantly with the decrease in DNA damage in Aβ42-treated cells. Our data clearly show that PPARα activation prevents DNA damage and neuronal cell apoptosis by decreasing the expression and translocation of AIF/Endo G to the nucleus in a caspase-3- and p53-independent pathway in the NT2N cell model. This role of PPARα in promoting neuron survival suggests a possible clinical application in treating Aβ42-associated neurotoxicity in Alzheimer’s disease.

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Abbreviations

PPARα:

Peroxisome proliferator-activated receptor alpha

Aβ:

Amyloid-β

AD:

Alzheimer’s disease

AIF:

Apoptosis-inducing factor

Endo G:

Endonuclease G

DMSO:

Dimethyl sulfoxide

RA:

All-trans retinoic acid

DMEM:

Dulbecco’s modified Eagle’s medium

NT2N:

Post-mitotic neuronal cells

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Acknowledgments

This study was supported by research Grants from the China Medical University (CMU95-094) and the Taiwan Department of Health, China Medical University Hospital Cancer Research Center of Excellence (DOH102-TD-C-111-005). We are grateful for the technical assistance from Dr. Chingju Lin and Mr. Derek Yi in quantifying the intensity of confocal images.

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, China Medical University, Taichung, 40402, Taiwan, ROC

    Ya-Hsin Cheng

  2. Department of Family Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung, Taiwan, ROC

    Shih-Wei Lai

  3. Department of Biochemistry, School of Medicine, China Medical University, 91 Shueh-Shih Rd., Taichung, 40402, Taiwan, ROC

    Pei-Yi Chen, Jia-Hao Chang & Nai Wen Chang

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  1. Ya-Hsin Cheng
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  2. Shih-Wei Lai
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Correspondence to Nai Wen Chang.

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The Ya-Hsin Cheng and Shih-Wei Lai had equal contribution.

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Cheng, YH., Lai, SW., Chen, PY. et al. PPARα Activation Attenuates Amyloid-β-Dependent Neurodegeneration by Modulating Endo G and AIF Translocation. Neurotox Res 27, 55–68 (2015). https://doi.org/10.1007/s12640-014-9485-9

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