Abstract: The phosphorylation of Amyloid Precursor Protein (APP) at Thr668 plays a key role in APP metabolism that is highly relevant to AD. The c-Jun-N-terminal kinase (JNK), glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (Cdk5) can all be responsible for this phosphorylation. These kinases are activated by excitotoxic stimuli fundamental hallmarks of AD. The exposure of cortical neurons to a high dose of NMDA (100 μM) for 30’-45’ led to an increase of P-APP Thr668. During NMDA stimulation APP hyperphosphorylation has to be assigned to GSK-3β activity, since addition of L803-mts, a substrate competitive inhibitor of GSK-3β reduced APP phosphorylation induced by NMDA. On the contrary, inhibition of JNK and Cdk5 with D-JNKI1 and Roscovitine respectively did not prevent NMDA-induced P-APP increase. These data show a tight connection, in excitotoxic conditions, between APP metabolism and the GSK-3β signaling pathway.
Keywords: APP; NMDA; GSK-3β; JNK; Cdk5
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Ploia, C.; Sclip, A.; Colombo, A.; Repici, M.; Gardoni, F.; Di Luca, M.; Forloni, G.; Antoniou, X.; Borsello, T. Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons. Pharmaceuticals 2010, 3, 42-58.
Ploia C, Sclip A, Colombo A, Repici M, Gardoni F, Di Luca M, Forloni G, Antoniou X, Borsello T. Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons. Pharmaceuticals. 2010; 3(1):42-58.
Ploia, Cristina; Sclip, Alessandra; Colombo, Alessio; Repici, Mariaelena; Gardoni, Fabrizio; Di Luca, Monica; Forloni, Gianluigi; Antoniou, Xanthi; Borsello, Tiziana. 2010. "Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons." Pharmaceuticals 3, no. 1: 42-58.