Inhibition of Notch Ligand Jagged 1 on Astrocytes : Implication on Inflammation and Regeneration in Neurodegenerative Disorders
Coordinating Institution:
Université du Luxembourg
Contracting Partner(s):
CRP-Santé ,
Axoglia Therapeutics S.A.
From: 01/01/2009
To: 31/12/2011
Budget: 341,000.00€
Contact(s):
Morga Eleonora
Progress Summary 2009
Many neurodegenerative diseases are underpinned by a dysregulated inflammatory response in the central nervous system (CNS), however, it is imperative that this process is tightly controlled. The inappropriate or chronic deployment of the inflammatory system can lead to a loss of its protective and reparative function and its emergence as a destructive force in pathogenic processes such as multiple sclerosis and Alzheimer’s disease. Astrocytes, the most abundant glial cell population, are essential for brain homeostasis and neuronal function.
Astrocytes are activated in response to acute brain insults and in the course of chronic neurodegenerative diseases. In the injured CNS, astrocytes appear as a key component of reactive gliosis, which is a major impediment for regeneration. The reactive gliosis seems to reexpress some of the processes observed during the development. The Notch signalling pathway is a mechanism implicated in many of these developmental processes, one of them is the control of the astrocytes differentiation. The Notch pathway is a highly conserved and ubiquitous signalling system that regulates cell fates. Although the Notch family of receptors and their ligands have initially been described in the context of the CNS development, few studies have yet documented the role of the Notch pathway in the control of astrocytes behaviour during neurodegenerative diseases. Recent results show that the reexpression of components of this pathway in the multiple sclerosis lesions create an environment that inhibits the final stages of oligodendrocyte maturation and so impedes the remyelination and regeneration. We showed that the inhibition of the Notch ligand, Jagged1, on astrocytes inhibits the gliosis and inhibits the inflammatory reaction on activated astrocytes.
Microarray analysis revealed several clusters of genes involved in various cellular processes such as immune response, cell signaling, cell adhesion and many others were altered by the inhibition of the Notch pathway. After having established the model of a cortical stab wound injury, we studied the effect of Jagged1 inhibition in vivo. Preliminary results show us that siRNA Jagged1 is able to inhibit the GFAP expression induced in reactive gliosis. We are further preparing an alternative in vivo model to study the effect of Jagged1 inhibition in an Jag1-/- mice generated from the Jag1lox/lox mice by Cre recombinase expression. The crossbreeding and genotyping are currently being performed. The aim of this project is to understand the implication of the Notch pathway in the adult CNS, especially during diseases with inflammatory andneurodegenerative components.
Refereed Scientific Publications:
Jagged1 regulates the activation of astrocytes via modulation of NFkappaB and JAK/STAT/SOCS pathways. Morga E, Mouad-Amazzal L, Felten P, Heurtaux T, Moro M, Michelucci A, Gabel S, Grandbarbe L, Heuschling P. Glia. 2009 Dec;57(16):1741-53.
Other Publications: none
Figure 1: Immunofluorescent staining of cultured astrocytes : cells were immunostained with antibodies against GFAP (green) and N-Cadherin (red)
Figure 2: siRNA Jagged1 injection inhibits GFAP expression in injured brain. Confocal analysis of GFAP (red) immunolabeling on cryosections 48 hours after induction of a cortical stab wound injury using stereotaxic method. Mice treated with siRNA J1 (right) show a strong decrease of GFAP expression compared to mice treated with siRNA neg control (left). Magnification 10X.