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.
Highlights
Lipids are a heterogeneous group of molecules that are ubiquitous components of cellular membranes
Inhibitors of protein kinase C (PKC; chelerythrine chloride), glycogen synthase kinase3 (GSK3; SB216763), Ca2+/calmodulin-dependent protein kinase II (CaMKII; KN62), and protease as well as phosphatase inhibitor cocktails were supplied by Calbiochem (San Diego, CA, USA). 6-Cyano-7-nitroquinoxaline-2,3dione disodium (CNQX) and picrotoxin were purchased from Sigma
0 68 dependent on GluN2B receptor activation and calcium mobilization, we investigated whether acid ceramidase inhibitor (ACI) can exert its action via intracellular pathways known to be regulated by calcium ions, namely, GSK3, PKC, and CaMKII pathways
Summary
Lipids are a heterogeneous group of molecules that are ubiquitous components of cellular membranes. Several studies over the past decades led to the concept that lipids and lipidderived molecules are more than purely structural elements and exhibit crucial functions in signal transduction and cell regulation. Ceramide, which is the core structure of sphingolipids, plays an important second messenger role in a wide range of cellular functions, including proliferation, adhesion, and cell differentiation [1]. The abnormal accumulation of amyloid β-peptide into senile (or amyloid) plaques is the main pathogenic event that occurs in all forms of Alzheimer’s disease. It has been suggested that ceramide elevation, Aβ formation, and Tau toxicity synergize to induce neuronal dysfunction in Alzheimer’s disease [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
