title: Blockade of lysosomal acid ceramidase induces GluN2B-dependent Tau phosphorylation in rat hippocampal slices.
abstract: The lysosomal acid ceramidase, an enzyme known to limit intracellular ceramide accumulation, has been reported to be defective in neurodegenerative disorders. We show here that rat hippocampal slices, preincubated with the acid ceramidase inhibitor (ACI) d-NMAPPD, exhibit increased N-methyl-D-aspartate (NMDA) receptor-mediated field excitatory postsynaptic potentials (fEPSPs) in CA1 synapses. The ACI by itself did not interfere with either paired pulse facilitation or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated fEPSPs, indicating that its influence on synaptic transmission is postsynaptic in origin and specific to the NMDA subtype of glutamate receptors. From a biochemical perspective, we observed that Tau phosphorylation at the Ser262 epitope was highly increased in hippocampal slices preincubated with the ACI, an effect totally prevented by the global NMDA receptor antagonist D/L(-)-2-amino-5-phosphonovaleric acid (AP-5), the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), and the GluN2B (but not the GluN2A) receptor antagonist RO25-6981. On the other hand, preincubation of hippocampal slices with the compound KN-62, an inhibitor known to interfere with calcium/calmodulin-dependent protein kinase II (CaMKII), totally abolished the effect of ACI on Tau phosphorylation at Ser262 epitopes. Collectively, these results provide experimental evidence that ceramides play an important role in regulating Tau phosphorylation in the hippocampus via a mechanism dependent on GluN2B receptor subunits and CaMKII activation.
authors.affiliation: Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7.
authors.forename: Marie-Elaine
authors.initials: ME
authors.lastname: Laurier-Laurin
authors.affiliation: Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7.
authors.forename: Audrée
authors.identifier: 0000-0003-2058-0607
authors.initials: A
authors.lastname: De Montigny
authors.affiliation: Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Attiori Essis
authors.affiliation: Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7.
authors.forename: Michel
authors.initials: M
authors.lastname: Cyr
authors.affiliation: Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7.
authors.forename: Guy
authors.identifier: 0000-0001-7514-9633
authors.initials: G
authors.lastname: Massicotte
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000201:enzymology / Q000502:physiology*; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D009226:Myristates / Q000494:pharmacology; D010766:Phosphorylation; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C454759:2-N-myristoylamino-1-(4-nitrophenyl)-1,3-propandiol; D009226:Myristates; C121001:NR2B NMDA receptor; D011412:Propanolamines; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D055573:Acid Ceramidase; C526736:Asah1 protein, rat