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

Cristina Ploia; Alessandra Sclip; Alessio Colombo; Mariaelena Repici; Fabrizio Gardoni; Monica Di Luca; Gianluigi Forloni; Xanthi Antoniou; Tiziana Borsello

doi:10.3390/ph3010042

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

Cristina Ploia, Alessandra Sclip, Alessio Colombo, Mariaelena Repici, Fabrizio Gardoni, Monica Di Luca, Gianluigi Forloni, Xanthi Antoniou, Tiziana Borsello

College of Health and Life Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	42-58
Number of pages	17
Journal	Pharmaceuticals
Volume	3
Issue number	1
DOIs	https://doi.org/10.3390/ph3010042
Publication status	Published - 7 Jan 2010

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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Role of Glycogen Synthase
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
Final published version, 366 KBLicence: CC BY 3.0

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@article{e40a1158aa5e4c3f9426c6bb7df01154,

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

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.",

author = "Cristina Ploia and Alessandra Sclip and Alessio Colombo and Mariaelena Repici and Fabrizio Gardoni and {Di Luca}, Monica and Gianluigi Forloni and Xanthi Antoniou and Tiziana Borsello",

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T1 - Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons

AU - Ploia, Cristina

AU - Sclip, Alessandra

AU - Colombo, Alessio

AU - Repici, Mariaelena

AU - Gardoni, Fabrizio

AU - Di Luca, Monica

AU - Forloni, Gianluigi

AU - Antoniou, Xanthi

AU - Borsello, Tiziana

N1 - This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

PY - 2010/1/7

Y1 - 2010/1/7

N2 - 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.

AB - 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.

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JO - Pharmaceuticals

JF - Pharmaceuticals

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ER -

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

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