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Medical Forum / Diseases and Disorders / Alzheimer's / April 2008Oxidative Stress-activated JNK
Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma -secretase. Shen C, Chen Y, Liu H, Zhang K, Zhang T, Lin A, Jing N J Biol Chem 2008 Apr 23. Accumulation of senile plaques composed of amyloid beta-peptide (Abeta) is a pathological hallmark of Alzheimer's disease (AD), and Abeta is generated through the sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase. Although oxidative stress has been implicated in AD pathogenesis by inducing Abeta production, the underlying mechanism remains elusive. Here we show that the pro-oxidant hydrogen peroxide (H2O2) promotes Abeta production through c-Jun N-terminal kinase (JNK)-dependent activation of gamma-secretase. Treatment with H2O2 induced significant increase in the levels of intracellular and secreted Abeta in human neuroblastoma SH-SY5Y cells. While gamma-secretase-mediated cleavage of APP or C99 was enhanced upon H2O2 treatment, expression of APP or its alpha-/beta-secretase-mediated cleavage was not affected. Silencing of the stress-activated JNK by siRNA or the specific JNK inhibitor SP600125 reduced H2O2-induced gamma-secretase-mediated cleavage of APP. JNK activity was augmented in human brain tissues from AD patients, and active JNK located surrounding the senile plaques in the brain of AD model mouse. Our data suggest that oxidative stress-activated JNK may contribute to senile plaques expansion through the promotion of gamma-secretase-mediated APP cleavage and Abeta production. The Journal of biological chemistry [J Biol Chem] -------------------------------------------------------------------------------- Who loves ya. Tom Jesus Was A Vegetarian! http://tinyurl.com/2r2nkh Man Is A Herbivore! http://tinyurl.com/a3cc3 DEAD PEOPLE WALKING http://tinyurl.com/zk9fk On Apr 26, 8:07 am, "ironjust...@aol.com" <ironjust...@aol.com> wrote: JNK-dependent activation of gamma -secretase. << "inhibition of JNK signaling achieved through iron sequestration" <<snip>> Our results suggest modulation of iron metabolism as a potential approach for anti-inflammatory therapy. <<snip>> Cell. 2004 Nov 12;119(4):529-42. Related Articles, Links Ferritin Heavy Chain Upregulation by NF-kappaB Inhibits TNFalpha- Induced Apoptosis by Suppressing Reactive Oxygen Species. Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, Jayawardena S, De Smaele E, Cong R, Beaumont C, Torti FM, Torti SV, Franzoso G. The Ben May Institute for Cancer Research and The University of Chicago, 924 East 57th Street, Chicago, IL 60637 USA. During inflammation, NF-kappaB transcription factors antagonize apoptosis induced by tumor necrosis factor (TNF)alpha. This antiapoptotic activity of NF-kappaB involves suppressing the accumulation of reactive oxygen species (ROS) and controlling the activation of the c-Jun N-terminal kinase (JNK) cascade. However, the mechanism(s) by which NF-kappaB inhibits ROS accumulation is unclear. We identify ferritin heavy chain (FHC)-the primary iron storage factor-as an essential mediator of the antioxidant and protective activities of NF-kappaB. FHC is induced downstream of NF-kappaB and is required to prevent sustained JNK activation and, thereby, apoptosis triggered by TNFalpha. FHC-mediated inhibition of JNK signaling depends on suppressing ROS accumulation and is achieved through iron sequestration. These findings establish a basis for the NF-kappaB-mediated control of ROS induction and identify a mechanism by which NF-kappaB suppresses proapoptotic JNK signaling. Our results suggest modulation of FHC or, more broadly, of iron metabolism as a potential approach for anti-inflammatory therapy. PMID: 15537542 [PubMed - in process] -------------------------------------------------------------------------- Who loves ya. Tom Jesus Was A Vegetarian! http://tinyurl.com/2r2nkh Man Is A Herbivore! http://tinyurl.com/a3cc3 DEAD PEOPLE WALKING http://tinyurl.com/zk9fk > Hydrogen peroxide promotes Abeta production through JNK-dependent > activation of gamma -secretase. [quoted text clipped - 34 lines] > > DEAD PEOPLE WALKINGhttp://tinyurl.com/zk9fk |
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