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

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)42-58
Number of pages17
JournalPharmaceuticals
Volume3
Issue number1
DOIs
Publication statusPublished - 2010

Fingerprint

Glycogen Synthase Kinase 3
Amyloid beta-Protein Precursor
N-Methylaspartate
Neurons
Cyclin-Dependent Kinase 5
JNK Mitogen-Activated Protein Kinases
Phosphorylation
Phosphotransferases

Keywords

  • APP
  • Cdk5
  • GSK-3β
  • JNK
  • NMDA

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science

Cite this

Role of glycogen synthase kinase-3β in APP hyperphosphorylation induced by NMDA stimulation in cortical neurons. / Ploia, Cristina; Sclip, Alessandra; Colombo, Alessio; Repici, Mariaelena; Gardoni, Fabrizio; di Luca, Monica; Forloni, Gianluigi; Antoniou, Xanthi; Borsello, Tiziana.

In: Pharmaceuticals, Vol. 3, No. 1, 2010, p. 42-58.

Research output: Contribution to journalArticle

Ploia, Cristina ; Sclip, Alessandra ; Colombo, Alessio ; Repici, Mariaelena ; Gardoni, Fabrizio ; di Luca, Monica ; Forloni, Gianluigi ; Antoniou, Xanthi ; Borsello, Tiziana. / Role of glycogen synthase kinase-3β in APP hyperphosphorylation induced by NMDA stimulation in cortical neurons. In: Pharmaceuticals. 2010 ; Vol. 3, No. 1. pp. 42-58.
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