Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation.
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.
Medina
Manel G
MG
Unitat de Biologia Cel.lular i Molecular, IMIM, Barcelona, Spain.
Ledesma
Maria Dolores
MD
Domínguez
Jorge E
JE
Medina
Miguel
M
Zafra
Delia
D
Alameda
Francesc
F
Dotti
Carlos G
CG
Navarro
Pilar
P
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D051381:Rats; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016875:tau Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D010959:Tissue Plasminogen Activator