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

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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.

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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

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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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Correspondence to Carmela R. Abraham.

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Zeldich, E., Chen, CD., Avila, R. et al. The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination. J Mol Neurosci 57, 185–196 (2015). https://doi.org/10.1007/s12031-015-0598-2

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