Article
- The EMBO Journal (2005) 24, 1706 - 1716
- doi:10.1038/sj.emboj.7600650
Published online: 21 April 2005
Subject Categories:
Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation
Manel G Medina1,a, Maria Dolores Ledesma2,a, Jorge E Domínguez3, Miguel Medina4, Delia Zafra3, Francesc Alameda5, Carlos G Dotti2 and Pilar Navarro1
- Unitat de Biologia Cel.lular i Molecular, IMIM, Barcelona, Spain
- Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, Orbassano (Turin), Italy
- IRBB-Parc Científic, Universitat de Barcelona, Barcelona, Spain
- NeuroPharma S.A., Tres Cantos, Madrid, Spain
- Departament Anatomia Patológica, Hospital del Mar, Barcelona, Spain
Correspondence to:
Pilar Navarro, Unitat Biologia Cel.lular i Molecular, Institut Municipal d'Investigació Mèdica, Dr Aiguader, 80, 08003 Barcelona, Spain. Tel.: +34 93 2211009; Fax: +34 93 2213237; E-mail: pnavarro@imim.es
aThese two authors contributed equally to this work
Received 7 July 2004; Accepted 24 March 2005
Abstract
Tissue plasminogen activator (tPA) is the main activator of plasminogen into plasmin in the brain where it may have beneficial roles but also neurotoxic effects that could be plasmin dependent or not. Little is known about the substrates and pathways that mediate plasmin-independent tPA neurotoxicity. Here we show in primary hippocampal neurons that tPA promotes a catalytic-independent activation of the extracellular regulated kinase (Erk)1/2 signal transduction pathway through the N-methyl-D-aspartate receptor, G-proteins and protein kinase C. This results in GSK3 activation in a process that requires de novo synthesis of proteins, and leads to tau aberrant phosphorylation, microtubule destabilization and apoptosis. Similar effects are produced by amyloid aggregates in a tPA-dependent manner, as demonstrated by pharmacological treatments and in wt and tPA-/- mice neurons. Consistently, in Alzheimer's disease (AD) patients' brains, high levels of tPA colocalize with amyloid-rich areas, activated Erk1/2 and phosphorylated tau. This is the first demonstration of an intracellular pathway by which tPA triggers kinase activation, tau phosphorylation and neurotoxicity, suggesting a key role for this molecule in AD pathology.
Keywords:
- A
, - Alzheimer's disease,
- Erk1/2,
- tau phosphorylation,
- tPA
- A
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