JNK activation is associated with intracellular beta-amyloid accumulation.
c-Jun has been implicated in the pathogenesis of Alzheimer's disease (AD), but the upstream cascade leading to c-Jun activation in AD is not known. Activation of c-Jun N-terminal kinase (JNK) is obviously a candidate for the upstream event. We tested this possibility focusing on PS1-linked AD. First, we observed that JNK is actually activated in cerebral neurons of PS1-linked AD patients, using immunohistochemistry and Western blot analyses with anti-activated JNK antibodies. We analyzed the relationship between beta-amyloid (beta A) and JNK activation by using aged transgenic mice overexpressing mutant (M146L) PS1 and human AD brains. The mice showed no neuronal loss but a very few diffuse beta A deposits, corresponding to the early stage of PS1-linked AD brain. Some neurons were reactive for anti-beta A antibodies in the cerebral cortex. Interestingly, JNK activation was observed in neurons showing intracellular beta A immunoreactivity in transgenic mice. Association between intracellular beta A and JNK activation was confirmed in cortical neurons of sporadic and PS1-linked AD patients. Furthermore, introduction of beta A peptides into the primary culture cortical neurons induced JNK activation and cell death. Collectively, these results suggested that intracellular beta A accumulation might trigger JNK activation leading to neuronal death.
Shoji
M
M
Toyama Pharmaceutical Co. 2-4-1, Shimo-okui, Toyama 930-8508, Japan.
Iwakami
N
N
Takeuchi
S
S
Waragai
M
M
Suzuki
M
M
Kanazawa
I
I
Lippa
C F
CF
Ono
S
S
Okazawa
H
H
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D010446:Peptide Fragments / Q000494:pharmacology; D053764:Presenilin-1; D015398:Signal Transduction / Q000502:physiology
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases