Skip to main content
SpringerLink
Log in

Differential Expression of Klotho in the Brain and Spinal Cord is Associated with Total Antioxidant Capacity in Mice with Experimental Autoimmune Encephalomyelitis

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Recently, we reported a positive correlation between Klotho, as an anti-aging protein, and the total antioxidant capacity (TAC) in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. However, there is no information about the Klotho and TAC changes within the central nervous system (CNS). Thus, the current study aimed to employ an experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice using MOG35–55 peptide to examine the relationship between Klotho and TAC within the CNS. To this end, the brain and spinal cord were obtained at the onset and peak stages of EAE as well as non-EAE mice (sham/control groups). The Klotho expression was assessed in the brain and spinal cord of different experimental groups at mRNA (qPCR) and protein (ELISA) levels. Also, TAC level was determined in the tissues of different experimental groups. The results showed that Klotho expression in the brain at the onset and peak stages of EAE were significantly lower than that in non-EAE mice. Conversely, Klotho expression in the spinal cord at the onset of EAE was significantly higher than that of non-EAE mice, while Klotho was comparable at the peak stage of EAE and non-EAE mice. The pattern of TAC alteration in the brain and spinal cord of EAE mice was similar to that of Klotho expression. In conclusion, for the first time, this study demonstrated a significant positive correlation between Klotho and TAC changes during the pathogenesis of EAE. It is suggested that Klotho may have neuroprotective activity through the regulation of redox system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Ahmadi M, Aleagha MSE, Harirchian MH, Yarani R, Tavakoli F, Siroos B (2016) Multiple sclerosis influences on the augmentation of serum Klotho concentration. J Neurol Sci 362:69–72

    Article  CAS  Google Scholar 

  • Aleagha MSE, Siroos B, Ahmadi M, Balood M, Palangi A, Haghighi AN, Harirchian MH (2015) Decreased concentration of Klotho in the cerebrospinal fluid of patients with relapsing–remitting multiple sclerosis. J Neuroimmunol 281:5–8

    Article  Google Scholar 

  • Balasubramanian P, Longo VD (2010) Linking Klotho, Nrf2, MAP kinases and aging. Aging (Albany NY) 2(10):632–633

    Article  Google Scholar 

  • Benzie IF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239(1):70–76

    Article  CAS  Google Scholar 

  • Bernardes D, Oliveira-Lima OC, da Silva TV, Faraco CCF, Leite HR, Juliano MA et al (2013) Differential brain and spinal cord cytokine and BDNF levels in experimental autoimmune encephalomyelitis are modulated by prior and regular exercise. J Neuroimmunol 264(1):24–34

    Article  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1–2):248–254

    Article  CAS  Google Scholar 

  • Cararo-Lopes MM, Mazucanti CHY, Scavone C, Kawamoto EM, Berwick DC (2017) The relevance of α-KLOTHO to the central nervous system: some key questions. Ageing Res Rev 36:137–148

    Article  CAS  Google Scholar 

  • Chen C-D, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, Bansal R (2013) The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 33(5):1927–1939

    Article  CAS  Google Scholar 

  • Christy AL, Walker ME, Hessner MJ, Brown MA (2013) Mast cell activation and neutrophil recruitment promotes early and robust inflammation in the meninges in EAE. J Autoimmun 42:50–61

    Article  CAS  Google Scholar 

  • Gilgun-Sherki Y, Melamed E, Offen D (2004) The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol 251(3):261–268

    Article  CAS  Google Scholar 

  • Grigoriadis N, Pesch V (2015) A basic overview of multiple sclerosis immunopathology. Eur J Neurol 22(S2):3–13

    Article  Google Scholar 

  • Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N et al (2004) Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 565(1–3):143–147

    Article  CAS  Google Scholar 

  • Karami M, Mehrabi F, Allameh A, Kakhki MP, Amiri M, Aleagha MSE (2017) Klotho gene expression decreases in peripheral blood mononuclear cells (PBMCs) of patients with relapsing-remitting multiple sclerosis. J Neurol Sci 381:305–307

    Article  CAS  Google Scholar 

  • Kuerten S, Kostova-Bales DA, Frenzel LP, Tigno JT, Tary-Lehmann M, Angelov DN, Lehmann PV (2007) MP4-and MOG: 35–55-induced EAE in C57BL/6 mice differentially targets brain, spinal cord and cerebellum. J Neuroimmunol 189(1):31–40

    Article  CAS  Google Scholar 

  • Kuerten S, Javeri S, Tary-Lehmann M, Lehmann PV, Angelov DN (2008) Fundamental differences in the dynamics of CNS lesion development and composition in MP4-and MOG peptide 35–55-induced experimental autoimmune encephalomyelitis. Clin Immunol 129(2):256–267

    Article  CAS  Google Scholar 

  • Kuro-o M (2008) Klotho as a regulator of oxidative stress and senescence. Biol Chem 389(3):233–241

    Article  CAS  Google Scholar 

  • Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T et al (1997) Mutation of the mouse Klotho gene leads to a syndrome resembling ageing. Nature 390(6655):45–51

    Article  CAS  Google Scholar 

  • Li S-A, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K (2004) Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct 29(4):91–99

    Article  CAS  Google Scholar 

  • Maekawa Y, Ishikawa K, Yasuda O, Oguro R, Hanasaki H, Kida I et al (2009) Klotho suppresses TNF-α-induced expression of adhesion molecules in the endothelium and attenuates NF-κB activation. Endocrine 35(3):341–346

    Article  CAS  Google Scholar 

  • Maltese G, Psefteli PM, Rizzo B, Srivastava S, Gnudi L, Mann GE, Siow R (2017) The anti-ageing hormone Klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells. J Cell Mol Med 21(3):621–627

    Article  CAS  Google Scholar 

  • Marques F, Mesquita SD, Sousa JC, Coppola G, Gao F, Geschwind DH et al (2012) Lipocalin 2 is present in the EAE brain and is modulated by natalizumab. Front Cell Neurosci 6:33

    Article  CAS  Google Scholar 

  • Moreno JA, Izquierdo MC, Sanchez-Niño MD, Suárez-Alvarez B, Lopez-Larrea C, Jakubowski A et al (2011) The inflammatory cytokines TWEAK and TNFα reduce renal Klotho expression through NFκB. J Am Soc Nephrol 22(7):1315–1325

    Article  CAS  Google Scholar 

  • Nagai T, Yamada K, Kim H-C, Kim Y-S, Noda Y, Imura A et al (2003) Cognition impairment in the genetic model of aging Klotho gene mutant mice: a role of oxidative stress. FASEB J 17(1):50–52

    Article  CAS  Google Scholar 

  • Rüther BJ, Scheld M, Dreymueller D, Clarner T, Kress E, Brandenburg LO, Fallier-Becker P (2017) Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression. Glia 65(12):1900–1913

    Article  Google Scholar 

  • Simmons SB, Liggitt D, Goverman JM (2014) Cytokine-regulated neutrophil recruitment is required for brain but not spinal cord inflammation during experimental autoimmune encephalomyelitis. J Immunol 193(2):555–563

    Article  CAS  Google Scholar 

  • Steinman L (1996) Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 85(3):299–302

    Article  CAS  Google Scholar 

  • Teocchi MA, Ferreira AÉD, de Oliveira EPDL, Tedeschi H, D’Souza-Li L (2013) Hippocampal gene expression dysregulation of Klotho, nuclear factor kappa B and tumor necrosis factor in temporal lobe epilepsy patients. J Neuroinflammation 10(1):53

    Article  CAS  Google Scholar 

  • Thurston RD, Larmonier CB, Majewski PM, Ramalingam R, Midura-Kiela M, Laubitz D et al (2010) Tumor necrosis factor and interferon-γ down-regulate Klotho in mice with colitis. Gastroenterology 138(4):1384–1394 e1382

    Article  CAS  Google Scholar 

  • Witkowski JM, Soroczyńska-Cybula M, Bryl E, Smoleńska Ż, Jóźwik A (2007) Klotho—a common link in physiological and rheumatoid arthritis-related aging of human CD4+ lymphocytes. J Immunol 178(2):771–777

    Article  CAS  Google Scholar 

  • Yao SQ, Li ZZ, Huang QY, Li F, Wang ZW, Augusto E, Zheng RY (2012) Genetic inactivation of the adenosine A2A receptor exacerbates brain damage in mice with experimental autoimmune encephalomyelitis. J Neurochem 123(1):100–112

    Article  CAS  Google Scholar 

  • Zargari M, Allameh A, Sanati MH, Tiraihi T, Lavasani S, Emadyan O (2007) Relationship between the clinical scoring and demyelination in central nervous system with total antioxidant capacity of plasma during experimental autoimmune encephalomyelitis development in mice. Neurosci Lett 412(1):24–28

    Article  CAS  Google Scholar 

  • Zeldich E, Chen C-D, Colvin TA, Bove-Fenderson EA, Liang J, Zhou TBT et al (2014) The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. J Biol Chem 289(35):24700–24715

    Article  CAS  Google Scholar 

  • Zeldich E, Chen C-D, Avila R, Medicetty S, Abraham CR (2015) The anti-aging protein Klotho enhances remyelination following cuprizone-induced demyelination. J Mol Neurosci 57(2):185–196

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was financially supported by a research grant (number 962470) provided by NIMAD (National Institute for Medical Research Development), Ministry of Health and Medical Education, Islamic Republic of Iran. Technical advice and support of the Ideal Tashkhis Atieh Company (Tehran, Iran) for immunoassays is acknowledged. The authors also wish to thank Dr. Shahab Moradkhani who assisted in the proof-reading of the revised version of this manuscript.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Box 14115, Tehran, PO, –111, Iran

    Mohammad Sajad Emami Aleagha & Abdolamir Allameh

  2. Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Hossein Harirchian

  3. Department of Biology, Sölvegatan 35, Building C, SE-223 62, Lund, Sweden

    Shahram Lavasani

  4. Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Mohammad Javan

Authors
  1. Mohammad Sajad Emami Aleagha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Hossein Harirchian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shahram Lavasani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad Javan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdolamir Allameh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abdolamir Allameh.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Emami Aleagha, M.S., Harirchian, M.H., Lavasani, S. et al. Differential Expression of Klotho in the Brain and Spinal Cord is Associated with Total Antioxidant Capacity in Mice with Experimental Autoimmune Encephalomyelitis. J Mol Neurosci 64, 543–550 (2018). https://doi.org/10.1007/s12031-018-1058-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-018-1058-6

Keywords

Search

Navigation