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Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons
Istituto di ricerche Farmacologiche \"Mario Negri\", Via La Masa 19, 20156 Milano, Italy
UMR 7102 Neurobiologie des Processus Adaptatifs, Universite P. et M. Curie, 9 quai St Bernard, 75005, Paris, France
Dipartimento Scienze Farmacologiche, Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy
* Author to whom correspondence should be addressed.
Received: 23 October 2009; in revised form: 3 December 2009 / Accepted: 5 January 2010 / Published: 7 January 2010
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.