Notch signaling pathway in the demyelination-remyelination process of the central nervous system.

ANA M. ADAMO

Huerta Grande

Congreso; Symposium: Axonal regeneration and remyelination: fact or fiction. XXVIII Congreso Anual de la Sociedad Argentina de Investigaci¨®n en Neurociencia; 2013

Sociedad Argentina de Investigaci¨®n en Neurociencia

Notch signaling pathway in the demyelination-remyelination process of the CNS Ana M. Adamo. Departamento de Qu¨ªmica Biol¨®gica, Facultad de Farmacia y Bioqu¨ªmica, UBA. IQUIFIB-CONICET. Oligodendroglial damage and demyelination are common pathological features characterizing white matter and neurodegenerative disorders. Identifying the signaling pathways involved in myelin repair through oligodendroglial progenitor cell (OPC) maturation is essential for the development of new therapies. We have investigated the role of the Notch signaling pathway in CNS demyelination and apotransferrin (aTf)-induced remyelination in two experimental models, focal lysolecithin (LPC)-induced and generalized cuprizone (CPZ)-induced demyelination in rats. Notch was found activated in Nestin-expressing neural progenitor cells and in NG2-expressing OPC in the subventricular zone (SVZ) and corpus callosum (CC) in both models. Notch activation seemed to be driven by Jagged1, which led to a high expression of downstream gene Hes5 in the SVZ of LPC-treated rats, and Hes1 in CPZ-demyelinated animals.  aTf injection induced remyelination, while the injection of the ¦Ã-secretase inhibitor reversed this effect.  In addition, 24 h after aTf injection, evidence showed Notch activation concomitantly with an increase in F3/contactin levels and the upregulation of the myelin-associated glycoprotein gene in the SVZ and CC of demyelinated rats. Collected evidence supports the participation of both canonical and non-canonical Notch signaling pathways in demyelination/remyelination. During demyelination, Notch activation was found to trigger Hes gene expression, which might promote OPC proliferation.  During aTf-induced remyelination, Notch activation seemed to be mediated by the expression of F3/contactin, which might induce aTf-mediated oligodendroglial maturation.