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Martin L.,University of Monastir | Page G.,Groupe de Recherche sur le Vieillissement Cerebral | Terro F.,University of Monastir | Terro F.,Laboratoire Dhistologie Et Of Cytogenetique
Neurochemistry International | Year: 2011

Overactivation of GSK3β (glycogen synthase kinase-3β) and downregulation of PP2A (protein phosphatase-2A) have been proposed to be involved in the abnormal tau phosphorylation and aggregation in Alzheimer's disease (AD). GSK3β and PP2A signaling pathways were reported to be interconnected. Targeting tau kinases was suggested to represent a therapeutic strategy for AD. Here, tau phosphorylation and neuronal apoptosis were induced in cortical cultured neurons by the inhibition of PP2A by okadaic acid (OKA). In this in vitro model of 'tau pathology' and neurodegeneration, we tested whether GSK3β and other tau kinases including DYRK1A and CDK5 were implicated. Our results show that the inhibitors of GSK3β, lithium and 6-BIO (6-bromoindirubin-3′-oxime), prevented OKA-induced tau phosphorylation and neuronal apoptosis. The implication of GSK3β in these OKA-induced effects was confirmed by its silencing by hairpin siRNA. By contrast, inhibition of DYRK1A (dual-specificity tyrosine-phosphorylation regulated kinase-1A) and CDK5 (cyclin-dependent kinase-5) reversed OKA-induced tau phosphorylation at certain sites but failed to prevent neuronal apoptosis. These results indicate that OKA-induced effects, especially neuronal apoptosis, are preferentially mediated by GSK3β. Furthermore, since chronic exposure to lithium and 6-BIO might be deleterious for neurons, we tested the effect of a new 6-BIO derivative, 6-BIBEO (6-bromoindirubin-3′-(2-bromoethyl)-oxime), which is much less cytotoxic and more selectively inhibits GSK3β compared to lithium and 6-BIO. We show that 6-BIBEO efficiently reversed OKA-induced tau phosphorylation and neuronal apoptosis. It will be interesting to test neuroprotection by 6-BIBEO in an in vivo model of tau pathology and neurodegeneration. © 2011 Elsevier B.V. All rights reserved.


Barrier L.,Groupe de Recherche sur le Vieillissement Cerebral | Ingrand S.,Groupe de Recherche sur le Vieillissement Cerebral | Fauconneau B.,Groupe de Recherche sur le Vieillissement Cerebral | Page G.,Groupe de Recherche sur le Vieillissement Cerebral
Neurobiology of Aging | Year: 2010

Altered sphingolipid metabolism plays an emergent role in the etiology of Alzheimer's disease (AD). In this study, we determined the levels of ceramides and other related-sphingolipids (sphingomyelins, sulfatides and galactosylceramides) in the cerebral cortex of an APPSL/PS1Ki mouse model of AD. The results demonstrate that ceramides accumulated in the cortex of APPSL/PS1Ki mice, but not in PS1Ki mice, whereas all others major sphingolipids (except galactosylceramides) were not altered in comparison with those from age-matched wild-type mice. Furthermore, as early as 3 months of age, female mice but not males, exhibit a strong increase in 2-hydroxy fatty acid-containing ceramides, whereas males display a significant elevation of non-hydroxy fatty acid ceramide species. Therefore, the gender differences in ceramide accumulation in the brain of mice expressing APPSL suggest that additional factors like modified ceramide metabolism may contribute to the increased propensity of females to develop AD. © 2008 Elsevier Inc.


PubMed | Groupe de Recherche sur le Vieillissement Cerebral
Type: | Journal: International journal of Alzheimer's disease | Year: 2011

There is evidence linking sphingolipid abnormalities, APP processing, and neuronal death in Alzheimers disease (AD). We previously reported a strong elevation of ceramide levels in the brain of the APP(SL)/PS1Ki mouse model of AD, preceding the neuronal death. To extend these findings, we analyzed ceramide and related-sphingolipid contents in brain from two other mouse models (i.e., APP(SL) and APP(SL)/PS1(M146L)) in which the time-course of pathology is closer to that seen in most currently available models. Conversely to our previous work, ceramides did not accumulate in disease-associated brain regions (cortex and hippocampus) from both models. However, the APP(SL)/PS1Ki model is unique for its drastic neuronal loss coinciding with strong accumulation of neurotoxic A isoforms, not observed in other animal models of AD. Since there are neither neuronal loss nor toxic A species accumulation in APP(SL) mice, we hypothesized that it might explain the lack of ceramide accumulation, at least in this model.


PubMed | Groupe de Recherche sur le Vieillissement Cerebral
Type: Journal Article | Journal: Neurobiology of aging | Year: 2010

Altered sphingolipid metabolism plays an emergent role in the etiology of Alzheimers disease (AD). In this study, we determined the levels of ceramides and other related-sphingolipids (sphingomyelins, sulfatides and galactosylceramides) in the cerebral cortex of an APP(SL)/PS1Ki mouse model of AD. The results demonstrate that ceramides accumulated in the cortex of APP(SL)/PS1Ki mice, but not in PS1Ki mice, whereas all others major sphingolipids (except galactosylceramides) were not altered in comparison with those from age-matched wild-type mice. Furthermore, as early as 3 months of age, female mice but not males, exhibit a strong increase in 2-hydroxy fatty acid-containing ceramides, whereas males display a significant elevation of non-hydroxy fatty acid ceramide species. Therefore, the gender differences in ceramide accumulation in the brain of mice expressing APP(SL) suggest that additional factors like modified ceramide metabolism may contribute to the increased propensity of females to develop AD.

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