Notch pathway and the effect of apotransferrin on remyelination

MILLANOVICH, V.L.; ADAMO, A.M.

Washington, DC, USA

Congreso; Neuroscience 2008; 2008

International Society for Neuroscience

In previous studies, we have demonstrated that a single intracranial injection (ICI) of apotransferrin (aTf) in 3-day-old rats produces an increase in the different myelin components. This promyelinating effect of aTf has been clearly shown in animals suffering demyelination after cuprizone (CPZ) feeding. ATf induces a marked increase in the myelin deposition in comparison with the spontaneous remyelination observed in control animals (C). In this study, we examined the possible participation of the Notch signalling pathway in the aTf mediated reversion of demyelination. Twenty one day old Wistar rats were fed a diet containing 0.6% CPZ during 2 weeks. After withdrawal of CPZ, animals were treated with either a single ICI of aTf or saline. At different times after ICI, rats were used to dissect the subventricular zone (SVZ) and corpus callosum (CC) for Western blot and the brain for immunohistochemistry. We studied the colocalization of Notch intracellular domain (NICD) with different oligodendroglial cells (OLGc) markers and the expression of down stream genes by RT-PCR to explore Notch pathway activation in the population of OLGc. Results show that the level of Notch receptor is lower in SVZ from brain of C in comparison with CPZ treated rats and that 6 h after the ICI of aTf the level of Notch increases in the SVZ from C while it decreases in CPZ treated animals. The ICI of aTf induces a significant decrease in the activation of Notch signalling pathway in SVZ NG2+ OLGc of CPZ demyelinated rats concomitantly with a decrease in the level of Jagged in GFAP+ cells in these animals. However, in CC the ICI of aTf induces an increase in the level of Deltex associated to NICD in CPZ treated animals, demonstrated by immunoprecipitation experiments using anti-Deltex specific antibody.  Preliminary results obtained with gama-secretase inhibitor injected with aTf in CPZ and control rats show similar outcomes in the remyelination process to those observed with the ICI of aTf. These results seem to indicate the involvement of Notch pathway in the aTf effect on the remyelination process.