beta-amyloid-induced neuronal apoptosis requires c-Jun N-terminal kinase activation

beta -Amyloid (A beta) has been strongly implicated in the pathophysiology of Alzheimer's disease (AD), but the means by which the aggregated form of this molecule induces neuronal death have not been fully defined. Here, we examine the role of the c-Jun N-terminal kinases (JNKs) and of their substr ate, c-Jun, in the death of cultured neuronal PC12 cells and sympathetic ne urons evoked by exposure to aggregated AP. The activities of JNK family mem bers increased in neuronal PC12 cells within 2 h of A beta treatment and re ached 3-4-fold elevation by 6 h. To test the role of these changes in death caused by A beta, we examined the effects of CEP-1347 (KT7515), an indoloc arbazole that selectively blocks JNK activation, inclusion of CEP-1347 (100 -300 nM) in the culture medium effectively blocked the increases in cellula r JNK activity caused by A beta and, at similar concentrations, protected b oth PC12 cells and sympathetic neurons from A beta -evoked-death. Effective protection required addition of CEP-1347 within 2 h of A beta treatment, i ndicating that the JNK pathway acts relatively proximally and as a trigger in the death mechanism. A dominant-negative c-Jun construct also conferred protection from AB-evoked death, supporting a model in which JNK activation contributes to death via activation of c-Jun. Finally, CEP-1347 blocked A beta -stimulated activation of caspase-2 and -3, placing these downstream o f JNK activation. These observations implicate the JNK pathway as a require d element in death evoked by A beta and hence identify it as a potential th erapeutic target in AD.