Klotho makes remyelination

Zeldich E, Chen CD, Avila R, Medicetty S, Abraham CR. The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination. J Mol Neurosci. 2015 Jun . [Epub ahead of print]

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. 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.

So another remyelinating possibility although if you read through the blog we have heard about this target before. Over the past two years we have had loads and loads of possibilities to remyelinate.
It takes time for these to filter through the system.but you know that

They looked in EAE and did not find any effect....Bravo, this is just what I would expect to see in early EAE because much of the early clinical disease in EAE has nothing whatsoever to do with demyelination, it is a conduction block (where nerves stop signalling transiently). Also disease would develop and them demyelination would occur so why would a remyelination drug stop disease before their was demeylination? 

In Lewis Rat EAE clinical paralysis occurs in the essential absence of demyelination and nerve loss..so the initial clinical signs do not have to be be ameliorated with remyelination agents.  

So many times we see studies in EAE where the so called neuroprotective and repair agent stops the disease developing. 

These often send the alarm bells ringing for me because it really says that the agents are (a) anti-inflammatory and then any remyelination seen is because it has allowed the natural repair mechanisms to do its job (b) or perhaps that experiment was a fluke and the EAE did not work properly, but because an effect on clinical disease was the expected result or (c) I am just a cynical *******. Maybe I will change my mind when I test a remyelination drug that works.....We have tried some and no effect.

However, this is one reason why it is good to have quality control in the system in EAE experiments. So often we see that the result in EAE is a result of the the level of disease in the control group, which makes the difference. 

Agents affecting these types of experiments tend to not translate...maybe because the data appears to be built on quicksand not stone.....cynical? Yes, creater of false hope...not so much.

Are there examples when remyelination agent had an ace effect on the the course of EAE but had no apparent anti-inflammatory effect in MS.....yes.