Different Protection of K252a and N-acetyl-L-cysteine Against Amyloid-β Peptide-induced Cortical Neuron Apoptosis Involving Inhibition of MLK3-MKK7-JNK3 Signal Cascades

Amyloid-beta peptide (A beta) has been implicated in the etiopathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms underlying A beta neurotoxicity remain to be elucidated. This study showed that A beta treatment resulted in the increased phosphorylation (activation) of MLK3, MKK7, and JNK3 in cultured cortical neurons, which characterized as biphasic activation (first peaked at 1 hr and second peaked at 12 hr after A beta treatment). K252a blocked A beta-induced neuronal apoptosis, both early and late phases of MLK3-MKK7-JNK3 activation, as well as downstream signal events involving p-JNKs nuclear translocation, c-Jun phosphorylation, and Bad translocation to the mitochondria. The neuroprotective effect of K252a on A beta-induced apoptosis was partially dependent on Akt activation. In contrast, antioxidant N-acetyl-L-cysteine (NAC) reduced early, but not late, MLK3-MKK7-JNK3 activation by A beta treatment and provided a weak neuroprotective ability in A beta-induced apoptosis. Taken together, A beta neurotoxicity is mainly due to MLK3-MKK7-JNK3 signal cascades. The late signal events of MLK3 activation after A beta treatment may play an important role in AD neuronal loss and will be a promising pharmacological target for AD therapeutic intervention. (C) 2008 Wiley-Liss, Inc.