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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
Author(s) -
Xu Yan,
Hou XiaoYu,
Liu Yong,
Zong YanYan
Publication year - 2009
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21909
Subject(s) - cysteine , apoptosis , peptide , chemistry , cortical neurons , neuron , cyclin dependent kinase 5 , neuroscience , microbiology and biotechnology , biochemistry , amyloid (mycology) , enzyme , biology , cell cycle , cyclin dependent kinase 2 , inorganic chemistry
Amyloid‐β peptide (Aβ) has been implicated in the etiopathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms underlying Aβ neurotoxicity remain to be elucidated. This study showed that Aβ 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 Aβ treatment). K252a blocked Aβ‐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 Aβ‐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 Aβ treatment and provided a weak neuroprotective ability in Aβ‐induced apoptosis. Taken together, Aβ neurotoxicity is mainly due to MLK3–MKK7–JNK3 signal cascades. The late signal events of MLK3 activation after Aβ treatment may play an important role in AD neuronal loss and will be a promising pharmacological target for AD therapeutic intervention. © 2008 Wiley‐Liss, Inc.