ABSTRACT
Title
The role of GSK-3 in inflammatory signalling in Alzheimer’s Disease
Authors
C . Bolondi
Doctorate School in Pharmacology and Toxicology
Dept. of Pharmacology- Alma Mater Studiorum, University of Bologna
Doctorate School in Pharmacology and Toxicology
Dept. of Pharmacology- Alma Mater Studiorum, University of Bologna
Abstract
Glycogen synthase kinase (GSK-3) plays a pivotal role in the pathogenesis of both sporadic and familial forms of Alzheimer’s Disease (AD). In particular, the over-activity of GSK-3 is correlated to hallmark characteristics of AD such as memory impairment, tau hyper-phosphorylation, increased b-amyloid production and local plaque-associated microglial-mediated inflammatory response. However, little is known about the signal trasduction pathways involved in the abnormal activation of GSK-3 and the role of GSK-3 in cerebral inflammatory response in AD [1,2]. Thus, in the present investigation we analyzed the effects of inflammatory mediators (TNF-a, IL-1band TGF-1b) released by activated microglia, on GSK-3 activation and tau hyper-phosphorylation in neuronal cell line and in primary cortical neurons. Then the study investigated if the stimulation with the inflammatory mediators could modify the GSK-3 activity through the modulation of the phosphatidylinositol 3 kinase/Akt (PI3K/Akt) signalling, that has been shown to act in a negative regulatory manner on the GSK-3 activity [3].
We found that IL-1band TGF-1btreatments in neuronal cell line and in primary cortical neurons lead to a decrease of GSK-3 activity that, at the same time, is associated with a positive modulation of the Akt activity and with a decrese in the level of tau phosphorylation.
Conversely, the TNF-atreatment in the same cellular models leads to an increase of GSK-3 activity that is correlated with a reduction of AKT activity but is not associated with an increase of phosphorylation of tau.
In accordance with scientific literature [3], these findings show that the microglia functions can be modulatory, protective or deleterious to the function of the surrounding cells, including astrocytes and neurons, but the balance between this roles is still not fully understood.
These preliminary results show that GSK-3 activity and the phosphorylation of tau can be modulated by the inflammatory mediators usually released by activated microglia. We propose that specific knowledge of mechanisms underlying inflammation and neuroprotection processes mediated by the different cytokines released by activated microglia would provide novel targets for therapeutic intervention in AD.
1) Hooper C et al. (2008)- J Neurochem. 2008 Mar; 104(6):1433-9. Epub 2007 Dec 18
2) Fuentalba RA et al. (2004)-Brain Res Brain Res Rev 2004Dec; 47(1-3):275-89.
3) Mercado-Gomez O et al. (2008)-Neurochem Res (2008) 33:1599-1609
We found that IL-1band TGF-1btreatments in neuronal cell line and in primary cortical neurons lead to a decrease of GSK-3 activity that, at the same time, is associated with a positive modulation of the Akt activity and with a decrese in the level of tau phosphorylation.
Conversely, the TNF-atreatment in the same cellular models leads to an increase of GSK-3 activity that is correlated with a reduction of AKT activity but is not associated with an increase of phosphorylation of tau.
In accordance with scientific literature [3], these findings show that the microglia functions can be modulatory, protective or deleterious to the function of the surrounding cells, including astrocytes and neurons, but the balance between this roles is still not fully understood.
These preliminary results show that GSK-3 activity and the phosphorylation of tau can be modulated by the inflammatory mediators usually released by activated microglia. We propose that specific knowledge of mechanisms underlying inflammation and neuroprotection processes mediated by the different cytokines released by activated microglia would provide novel targets for therapeutic intervention in AD.
1) Hooper C et al. (2008)- J Neurochem. 2008 Mar; 104(6):1433-9. Epub 2007 Dec 18
2) Fuentalba RA et al. (2004)-Brain Res Brain Res Rev 2004Dec; 47(1-3):275-89.
3) Mercado-Gomez O et al. (2008)-Neurochem Res (2008) 33:1599-1609