JNK activation is associated with intracellular β-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 (betaA) and JNK activation by using aged transgenic mice overexpressing mutant (M146L) PSI and human AD brains. The mice showed no neuronal loss but a very few diffuse betaA deposits, corresponding to the early stage of PS1-linked AD brain. Some neurons were reactive for anti-betaA antibodies in the cerebral cortex. Interestingly, JNK activation was observed in neurons showing intracellular betaA immunoreactivity in transgenic mice. Association between intracellular betaA and JNK activation was confirmed in cortical neurons of sporadic and PS1-linked AD patients. Furthermore, introduction of betaA peptides into the primary culture cortical neurons induced JNK activation and cell death. Collectively, these results suggested that intracellular betaA accumulation might trigger JNK activation leading to neuronal death. (C) 2000 Elsevier Science B.V. All rights reserved.