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Pharmaceuticals 2010, 3(1), 42-58; doi:10.3390/ph3010042
Article

Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons

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Received: 23 October 2009 / Revised: 3 December 2009 / Accepted: 5 January 2010 / Published: 7 January 2010
(This article belongs to the Special Issue Protein Kinase Inhibitors)
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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 APP; NMDA; GSK-3β; JNK; Cdk5
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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.

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