title: The neuroprotective effect of Klotho is mediated via regulation of members of the redox system.
abstract: 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 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 resistant to both cytotoxic insults, glutamate and oAβ, compared with neurons from wild-type littermates. An antioxidative 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 the 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. Down-regulation of Prx-2 expression using a lentivirus harboring shRNA almost completely abolished the ability of Klotho 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.
authors.affiliation: From the Department of Biochemistry.
authors.forename: Ella
authors.initials: E
authors.lastname: Zeldich
authors.affiliation: From the Department of Biochemistry.
authors.forename: Ci-Di
authors.initials: CD
authors.lastname: Chen
authors.affiliation: Program in Molecular Medicine, and.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Colvin
authors.affiliation: From the Department of Biochemistry.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Bove-Fenderson
authors.affiliation: From the Department of Biochemistry.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Tracey B
authors.initials: TB
authors.lastname: Tucker Zhou
authors.affiliation: From the Department of Biochemistry.
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
authors.affiliation: From the Department of Biochemistry, Program in Molecular Medicine, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118 cabraham@bu.edu.
authors.forename: Carmela R
authors.initials: CR
authors.lastname: Abraham
mesh_terms: D000818:Animals; D005260:Female; D005966:Glucuronidase / Q000502:physiology*; D000090265:Klotho Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Alzheimer Disease; Amyloid; Glutamate; Neuroprotection; Oxidative Stress