Active c-jun N-terminal kinase induces caspase cleavage of tau and additional phosphorylation by GSK-3beta is required for tau aggregation.
Neurofibrillary tangles (NFTs), comprising human intracellular microtubule-associated protein tau, are one of the hallmarks of tauopathies, including Alzheimer's disease. Recently, a report that caspase-cleaved tau is present in NFTs has led to the hypothesis that the mechanisms underlying NFT formation may involve the apoptosis cascade. Here, we show that adenoviral infection of tau into COS-7 cells induces activation of c-jun N-terminal kinase (JNK), followed by excessive phosphorylation of tau and its cleavage by caspase. However, JNK activation alone was insufficient to induce sodium dodecyl sulfate (SDS)-insoluble tau aggregation and additional phosphorylation by GSK-3beta was required. In SH-SY5Y neuroblastoma cells, overexpression of active JNK and GSK-3beta increased caspase-3 activation and cytotoxicity more than overexpression of tau alone. Taken together, these results indicate that, although JNK activation may be a primary inducing factor, further phosphorylation of tau is required for neuronal death and NFT formation in neurodegenerative diseases, including those characterized by tauopathy.
Laboratory for Alzheimer' Disease, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan.
Naruhiko
N
Sahara
Miyuki
M
Murayama
Boyoung
B
Lee
Jung-Mi
JM
Park
Sarita
S
Lagalwar
Lester I
LI
Binder
Akihiko
A
Takashima
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019556:COS Cells; D053148:Caspase 3 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D013501:Surface-Active Agents / Q000494:pharmacology; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D013501:Surface-Active Agents; D016875:tau Proteins; D012967:Sodium Dodecyl Sulfate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases