title: Anti-amyloidogenic effects of glycosphingolipid synthesis inhibitors occur independently of ganglioside alterations.
abstract: Evidence has suggested that ganglioside abnormalities may be linked to the proteolytic processing of amyloid precursor protein (APP) in Alzheimer's disease (AD) and that pharmacological inhibition of ganglioside synthesis may reduce amyloid β-peptide (Aβ) production. In this study, we assessed the usefulness of two well-established glycosphingolipid (GSL) synthesis inhibitors, the synthetic ceramide analog D-PDMP (1-phenyl 2-decanoylamino-3-morpholino-1-propanol) and the iminosugar N-butyldeoxynojirimycin (NB-DNJ or miglustat), as anti-amyloidogenic drugs in a human cellular model of AD. We found that both GSL inhibitors were able to markedly inhibit Aβ production, although affecting differently the APP cleavage. Surprisingly, the L-enantiomer of PDMP, which promotes ganglioside accumulation, acted similarly to D-PDMP to inhibit Aβ production. Concurrently, both D- and L-PDMP strongly and equally reduced the levels of long-chain ceramides. Altogether, our data suggested that the anti-amyloidogenic effects of PDMP agents are independent of the altered cellular ganglioside composition, but may result, at least in part, from their ability to reduce ceramide levels. Moreover, our current study established for the first time that NB-DNJ, a drug already used as a therapeutic for Gaucher disease (a lysosomal storage disorder), was also able to reduce Aβ production in our cellular model. Therefore, our study provides novel information regarding the possibilities to target amyloidogenic processing of APP through modulation of sphingolipid metabolism and emphasizes the potential of the iminosugar NB-DNJ as a disease modifying therapy for AD.
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; Université de Poitiers, Groupe de Recherche sur le Vieillissement Cérébral GRéViC EA3808, 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: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005732:Gangliosides / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D005732:Gangliosides; D009025:Morpholines; D017485:1-Deoxynojirimycin; C033110:RV 538; C059896:miglustat
keywords: APP processing; Alzheimer's disease; Amyloid-beta peptide; Ceramides; Gangliosides; Sphingolipids