The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System [Molecular Bases of Disease]

July 18th, 2014 by Zeldich, E., Chen, C.-D., Colvin, T. A., Bove-Fenderson, E. A., Liang, J., Tucker Zhou, T. B., Harris, D. A., Abraham, C. R.

Generation of reactive oxygen species (ROS), leading to oxidative damage and neuronal cell death plays an important role in the pathogenesis of neurodegenerative disorders including Alzheimer's disease. The present study aimed to examine the mechanism by which the anti-aging protein Klotho exerts neuroprotective effects against neuronal damage associated with neurodegeneration and oxidative stress. Pretreatment of rat primary hippocampal neurons and mouse hippocampal neuronal cell line HT22 with recombinant Klotho protected these cells from glutamate and oligomeric amyloid β (oAβ)-induced cytotoxicity. In addition, primary hippocampal neurons obtained from Klotho overexpressing mouse embryos were more resistent to both cytotoxic insults, glutamate and oAβ, compared to neurons from wild type littermates. An anti-oxidative stress array analysis of neurons treated with Klotho revealed that Klotho significantly enhances the expression of the thioredoxin/peroxiredoxin (Trx/Prx) system with the greatest effect on the induction of Prx-2, an antioxidant enzyme, whose increase was confirmed at the mRNA and protein levels. Klotho-induced phosphorylation of PI3K/Akt pathway, a pathway important in apoptosis and longevity, was associated with sustained inhibitory phosphorylation of the transcription factor forkhead box O3a (FoxO3a), and was essential for the induction of Prx-2. Downregulation of Prx-2 expression using a lentivirus harboring shRNA abolished Klotho's ability to rescue neurons from glutamate-induced death and significantly, but not completely, inhibited cell death mediated by oAβ, suggesting that Prx-2 is a key modulator of neuroprotection. Thus, our results demonstrate, for the first time, the neuroprotective role of Klotho and reveal a novel mechanism underlying this effect.