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 Thr668plays 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.
authors.affiliation: Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. cristina.ploia@marionegri.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ploia
authors.affiliation: Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. alessandra.sclip@marionegri.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sclip
authors.affiliation: Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. alessiovittorio.colombo@marionegri.it.
authors.forename: Alessio
authors.initials: A
authors.lastname: Colombo
authors.affiliation: UMR 7102 Neurobiologie des Processus Adaptatifs, Universite P. et M. Curie, 9 quai St Bernard, 75005, Paris, France. mr200@leicester.ac.uk.
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Repici
authors.affiliation: Dipartimento Scienze Farmacologiche, Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy. fabrizio.gardoni@unimi.it.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.affiliation: Dipartimento Scienze Farmacologiche, Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy. monica.diluca@unimi.it.
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
authors.affiliation: Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. gianluigi.forloni@marionegri.it.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.affiliation: Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. xanthi.antoniou@marionegri.it.
authors.forename: Xanthi
authors.initials: X
authors.lastname: Antoniou
authors.affiliation: Istituto di ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy. tiziana.borsello@marionegri.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Borsello
keywords: APP; Cdk5; GSK-3β; JNK; NMDA