title: PPARα activation attenuates amyloid-β-dependent neurodegeneration by modulating Endo G and AIF translocation.
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.
authors.affiliation: Department of Physiology, School of Medicine, China Medical University, Taichung, 40402, Taiwan, ROC.
authors.forename: Ya-Hsin
authors.initials: YH
authors.lastname: Cheng
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Lai
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chen
authors.forename: Jia-Hao
authors.initials: JH
authors.lastname: Chang
authors.forename: Nai Wen
authors.initials: NW
authors.lastname: Chang
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D051033:Apoptosis Inducing Factor; D047493:PPAR alpha; D010446:Peptide Fragments; D011743:Pyrimidines; C075222:amyloid beta-protein (1-42); C006253:pirinixic acid; D004706:Endodeoxyribonucleases; C052391:endonuclease G