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Journal of Molecular Neuroscience

, Volume 57, Issue 2, pp 185–196 | Cite as

The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination

  • Ella Zeldich
  • Ci-Di Chen
  • Robin Avila
  • Satish Medicetty
  • Carmela R. AbrahamEmail author
Article

Abstract

The current study examined whether overexpression of Klotho (KL) in transgenic mice can enhance remyelination following cuprizone-induced demyelination and improves the clinical outcome in experimental autoimmune encephalomyelitis (EAE). Demyelination was achieved by feeding transgenic mice overexpressing the transmembrane form of Klotho (KL-OE) and wild-type (WT) littermates cuprizone-containing chow for 6 weeks. The animals were then allowed to remyelinate for 3 weeks. Paraphenylenediamine staining and platelets-derived growth factor receptor α (PDGFRα) and glutathione S-transferase pi (GSTpi) immunohistochemistry were performed on corpus callosum (CC) sections for quantification of myelin and progenitor and mature oligodendrocytes, respectively. The EAE model was induced with the MOG35–55 peptide. The animals were scored daily for clinical symptoms for 30 days. Following 6 weeks of demyelination, both KL-OE mice and WT littermates demonstrated almost complete and comparable demyelination of the CC. However, the level of spontaneous remyelination was increased approximately two-fold in KL-OE mice, although no significant differences in the numbers of PDGFRα and GSTpi-positive cells were observed. Following EAE induction, Klotho overexpression did not affect the clinical scores, likely due to the different roles Klotho plays in the brain and spinal cord. Thus, increasing Klotho expression should be considered as a therapy for enhancing remyelination in the brains of individuals with multiple sclerosis.

Keywords

Multiple sclerosis Oligodendrocyte differentiation Myelin repair Small molecule compounds 

Abbreviations

CC

Corpus callosum

CSF

Cerebrospinal fluid

CNS

Central nervous system

EAE

Experimental autoimmune encephalomyelitis

ERK

Extracellular regulated kinase

GSTpi

Glutathione S-transferase pi

KL

Klotho

KL-OE

Klotho overexpressing

KL-KO

Klotho knockout

MOG

Myelin-oligodendrocyte glycoprotein

MS

Multiple sclerosis

OPC

Oligodendrocyte progenitor cell

OL

Oligodendrocyte

PDGFRα

Platelets-derived growth factor receptor α

PLP

Proteolipid protein

PPD

Paraphenylenediamine

sKL

Shed Klotho

TNF-α

Tumor necrosis factor α

WT

Wild type

IP

Intraperitoneal

Notes

Acknowledgments

We thank Dr. Makoto Kuro-o for the gift of the KL-OE mice and for reading the manuscript. We are grateful to Dr. Christina Khodr for her diligent help with establishing and maintaining KL-OE mice colony. This work was supported in part by a Boston University Ignition Award to CRA.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ella Zeldich
    • 1
  • Ci-Di Chen
    • 1
  • Robin Avila
    • 3
  • Satish Medicetty
    • 3
  • Carmela R. Abraham
    • 1
    • 2
    Email author
  1. 1.Departments of BiochemistryBoston University School of MedicineBostonUSA
  2. 2.Pharmacology and Experimental TherapeuticsBostonUSA
  3. 3.Renovo Neural Inc. ClevelandClevelandUSA

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