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

Abstract

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 substrate, c-Jun, in the death of cultured neuronal PC12 cells and sympathetic neurons evoked by exposure to aggregated A beta. The activities of JNK family members increased in neuronal PC12 cells within 2 h of A beta treatment and reached 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 indolocarbazole that selectively blocks JNK activation. Inclusion of CEP-1347 (100--300 nM) in the culture medium effectively blocked the increases in cellular JNK activity caused by A beta and, at similar concentrations, protected both PC12 cells and sympathetic neurons from A beta-evoked-death. Effective protection required addition of CEP-1347 within 2 h of A beta treatment, indicating 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 A beta-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 of JNK activation. These observations implicate the JNK pathway as a required element in death evoked by A beta and hence identify it as a potential therapeutic target in AD.

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

“…In primary hippocampal neurons, the levels of active JNK and phosphorylated IRS1 (Ser616) and tau (Ser422) are significantly increased by exposure to Aβ oligomers (Shoji et al ., 2000). Conversely, JNK inhibition is capable of reducing Aβ toxicity and ameliorating the major pathological features of AD (Troy et al ., 2001; Zhou et al ., 2015). In the present study, we found that intranasal insulin was revealed to target JNK activation in APP/PS1 mice.…”

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

“…Interestingly, the lack of effect of the c-Jun antisense oligonucleotide on caspase-2 and -3 activations lies, in contrast, with the previously reported inhibition of these caspases upon treatment with CEP-1347, an inhibitor of the c-Jun N-terminal kinase (JNK). 19,58 It could thus be postulated that the effect of CEP-1347 on these two caspases reflected disruption of the JNK action on a target different from c-Jun, such as activating transcription factor 2 or Elk1. 59 It should also be noticed that, despite its lack of effect on the activation of caspase-2 and -3, the c-Jun antisense oligonucleotide afforded protection of cortical neurons against Ab-induced apoptosis.…”

“…[40][41][42] Moreover, both c-Jun expression and activation were found to be increased following exposure of neurons to Ab, and recent data suggested a 12-Lipoxygenase and amyloid peptide toxicity A Lebeau et al critical role of this transcription factor in Ab-induced apoptosis. [17][18][19]43,44 We therefore investigated whether 12-LOX blockade could interfere with such an Ab-induced c-Jundependent apoptotic pathway in cortical cells.…”

“…15,16 Recent data further evidenced a major role of the transcription factor c-Jun in mediating Ab-induced apoptosis. [17][18][19] Overexpression of this factor was detected in neurons surrounding senile plaques. 20 However, the exact signaling pathways underlying Ab-induced apoptosis have not been fully elucidated yet.…”

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

“…However, the apoptotic process does not occur in JNK-knockout mice [222] or mice expressing a mutant form of c-Jun lacking the JNK phosphorylation site [15]. In addition, the indirect inhibition of JNK by CEP-1347 protected neuronal PC12 cells and sympathetic neurons in vitro from death following trophic factor withdrawal, beta-amyloid exposure, UV-radiation and oxidative stress [126,205]. Furthermore, CEP-1347 protected nigral neurons in vivo against MPP + -induced neuronal death [173] implicating again the involvement of JNK in neurodegeneration.…”