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

Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. [email protected].
Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. [email protected].
Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. [email protected].
Dipartimento Scienze Farmacologiche, Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy. [email protected].
Dipartimento Scienze Farmacologiche, Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy. [email protected].
Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. [email protected].
Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. [email protected].
Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. [email protected].

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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.

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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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

IS - 1

ER -

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

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