A role for c-Jun N-terminal kinase 1 (JNK1), but not JNK2, in the β-amyloid-mediated stabilization of protein p53 and induction of the apoptotic cascade in cultured cortical neurons

beta-Amyloid (Abeta) peptide has been shown to induce neuronal apoptosis; however, the mechanisms underlying Abeta-induced neuronal cell death remain to be fully elucidated. The stress-activated protein kinase, c-Jun N-terminal kinase (INK), is activated in response to cellular stress and has been identified as a proximal mediator of cell death. In the present study, expression of active JNK was increased in the nucleus and cytoplasm of Abeta-treated cells. Evaluation of the nature of the JNK isoforms activated by Abeta revealed a transient increase in JNK1 activity that reached its peak at 1 h and a later activation (at 24 h) of JNK2. The tumour suppressor protein, p53, is a substrate for JNK and can serve as a signalling molecule in apoptosis. In cultured cortical neurons, we found that Abeta increased p53 protein expression and phosphorylation of p53 at Ser(15). Thus it appears that Abeta increases p53 expression via phosphorylation-mediated stabilization of the protein. Given the lack of availability of a JNK inhibitor that can distinguish between JNK1- and JNK2-mediated effects, we employed antisense technology to deplete cells of JNK1 or JNK2 selectively. Using this strategy, the respective roles of JNK1 and JNK2 on the Abeta-mediated activation of the apoptotic cascade (i.e. p53 stabilization, caspase 3 activation and DNA fragmentation) were examined. The results obtained demonstrate a role for JNK1 in the Abeta-induced stabilization of p53, activation of caspase 3 and DNA fragmentation. In contrast, depletion of JNK2 had no effect on the proclivity of A to activate capase 3 or induce DNA fragmentation. These results demonstrate a significant role for JNK1 in Abeta-mediated induction of the apoptotic cascade in cultured cortical neurons.