title: Inhibition of GSK3β by pharmacological modulation of sphingolipid metabolism occurs independently of ganglioside disturbance in a cellular model of Alzheimer's disease.
abstract: Accumulating evidence implicates ganglioside and/or related-sphingolipid disturbance in the pathogenesis of Alzheimer's disease (AD). However, it is not known whether these lipidic alterations are connected with other important features of AD, such as deregulated insulin/Akt/GSK3 signaling. In this study, we have treated neuroglioma cells expressing the double Swedish mutation of human amyloid precursor protein (H4APPsw) with several glycosphingolipid (GSL)-modulating agents, and we have analyzed the impact of the aberrant ganglioside composition on the GSK3 activation state. We found that both ceramide analogs D- and L-PDMP (1-phenyl 2-decanoylamino-3-morpholino-1-propanol), which have opposite effects on ganglioside synthesis, selectively inhibited GSK3β via Ser9 phosphorylation independently of the upstream insulin/Akt pathway. Conversely, the iminosugar N-butyldeoxynojirimycin (NB-DNJ) which displayed similar reduction of gangliosides as D-PDMP, did not affect the phosphorylation state of GSK3β. Concurrently, while NB-DNJ did not modify the cellular ceramide content, both PDMP enantiomers strongly and equally reduced the levels of long-chain ceramide species. Altogether, our findings led us to hypothesize that the PDMP-induced altered ganglioside composition is not the principal mechanism involved in the inhibition of GSK3β, but seems to implicate, at least in part, their ability to reduce ceramide levels. Nevertheless, this study provides new information regarding the possibilities to target GSK3β through modulation of sphingolipid metabolism.
authors.affiliation: Université Laval, Faculté de médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada; Centre Hospitalier de l'Université Laval, Axe Neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; University of Poitiers, Groupe de Recherche sur le Vieillissement Cérébral, GRéViC EA 3808, Poitiers, France.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Noel
authors.affiliation: Université de Poitiers, UFR Médecine & Pharmacie, Service de Biochimie et Toxicologie, 6 rue de la Milétrie, TSA 51115, 86073 Poitiers cedex 9, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ingrand
authors.affiliation: Université de Poitiers, UFR Médecine & Pharmacie, Service de Biochimie et Toxicologie, 6 rue de la Milétrie, TSA 51115, 86073 Poitiers cedex 9, France. Electronic address: lbarrier@univ-poitiers.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Barrier
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005732:Gangliosides / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics*; D005910:Glioma / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013107:Sphingolipids / Q000378:metabolism*; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D005732:Gangliosides; D007004:Hypoglycemic Agents; D007328:Insulin; D009025:Morpholines; D013107:Sphingolipids; C033110:RV 538; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer's disease; Ceramides; Gangliosides; Glycogen synthase kinase 3; Sphingolipids