CEP‐1347/KT‐7515, an inhibitor of SAPK/JNK pathway activation, promotes survival and blocks multiple events associated with Aβ‐induced cortical neuron apoptosis

Abstract

Although the mechanism of neuronal death in Alzheimer's disease (AD) has yet to be elucidated, a putative role for c-jun in this process has emerged. Thus, it was of interest to delineate signal transduction pathway(s) which regulate the transcriptional activity of c-jun, and relate these to alternate gene inductions and biochemical processes associated with beta-amyloid (Abeta) treatment. In this regard, the survival promoting activity of CEP-1347, an inhibitor of the stress-activated/c-jun N-terminal (SAPK/JNK) kinase pathway, was evaluated against Abeta-induced cortical neuron death in vitro. Moreover, CEP-1347 was used as a pharmacologic probe to associate multiple biochemical events with Abeta-induced activation of the SAPK/JNK pathway. CEP-1347 promoted survival and blocked Abeta-induced activation of JNK kinase (MKK4, also known as MEK-4, JNKK and SEK1) as well as other downstream events associated with JNK pathway activation. CEP-1347 also blocked Abeta-induction of cyclin D1 and DP5 genes and blocked Abeta-induced increases in cytoplasmic cytochrome c, caspase 3-like activity and calpain activation. The critical time window for cell death blockade by CEP-1347 resided within the peak of Abeta-induced MKK4 activation, thus defining this point as the most upstream event correlated to its survival-promoting activity. Together, these data link the SAPK/JNK pathway and multiple biochemical events associated with Abeta-induced neuronal death and further delineate the point of CEP-1347 interception within this signal transduction cascade.