The phosphorylation of Amyloid Precursor Protein (APP) at Thr 668 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 Thr 668. 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.
Role of glycogen synthase kinase-3β in APP hyperphosphorylation induced by NMDA stimulation in cortical neurons / C. Ploia, A. Sclip, A. Colombo, M. Repici, F. Gardoni, M. Di Luca, G. Forloni, X. Antoniou, T. Borsello. - In: PHARMACEUTICALS. - ISSN 1424-8247. - 3:1(2010), pp. 42-58. [10.3390/ph3010042]
Role of glycogen synthase kinase-3β in APP hyperphosphorylation induced by NMDA stimulation in cortical neurons
F. Gardoni;M. Di Luca;T. Borsello
2010
Abstract
The phosphorylation of Amyloid Precursor Protein (APP) at Thr 668 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 Thr 668. 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.File | Dimensione | Formato | |
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