Pathological effects of glyoxalase I inhibition in SH-SY5Y neuroblastoma cells

被引:37
作者
Kuhla, Bjoern
Lueth, Hans-Joachim
Haferburg, Dietrich
Weick, Michael
Reichenbach, Andreas
Arendt, Thomas
Muench, Gerald
机构
[1] Univ Leipzig, Interdisciplinary Ctr Clin Res, IZKF, D-04103 Leipzig, Germany
[2] Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA
[3] Karl Marx Univ, Paul Flechsig Inst Brain Res, Dept Neuroanat, Leipzig, Germany
[4] Karl Marx Univ, Inst Biochem, D-7010 Leipzig, Germany
[5] Karl Marx Univ, Paul Flechsig Inst Brain Res, Dept Neurophysiol, Leipzig, Germany
[6] James Cook Univ N Queensland, Dept Biochem & Mol Biol, Townsville, Qld 4811, Australia
关键词
glyoxalase; 1; methylglyoxal; oxidative stress; okadaic acid; calcium; caspase-3; tau phosphorylation; protein phosphatases; Alzheimer's disease;
D O I
10.1002/jnr.20838
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In Alzheimer's disease (AD), in aging, and under conditions of oxidative stress, the levels of reactive carbonyl compounds continuously increase. Accumulating carbonyl levels might be caused by an impaired enzymatic detoxification system. The major dicarbonyl detoxifying system is the glyoxalase system, which removes methylglyoxal in order to minimize cellular impairment. Although a reduced activity of glyoxalase I was evident in aging brains, it is not known how raising the intracellular methylglyoxal level influences neuronal function and the phosphorylation pattern of tau protein, which is known to be abnormally hyperphosphorylated in AD. To simulate a reduced glyoxalase I activity, we applied an inhibitor of glyoxalase 1, p-bromobenzylglutathione cyclopentyl diester (p13rBzGSCp(2)), to SH-SY5Y neuroblastoma cells to induce chronically elevated methylglyoxal concentrations. We have shown that 10 mu M pBrBzGSCp(2) leads to a four-fold elevation of the methylglyoxal level after 24 hr. In addition, glyoxalase I inhibition leads to reduced cell viability, strongly retracted neuritis, increase in [Ca2+](i), and activation of caspase-3. However, pBrBzGSCP(2) did not lead to tau "hyper"-phosphorylation despite activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase but rather activated protein phosphatases 2 and induced tau dephosphorylation at the Ser(202)/Thr(205) and Ser(396)/Ser(404) epitopes. Preincubation with the carbonyl scavenger aminoguanidine prevented tau dephosphorylation, indicating the specific effect of methylglyoxal. Also, pretreatment with the inhibitor okadaic acid prevented tau dephosphorylation, indicating that methylglyoxal activates PP-2A. In summary, our data suggest that a reduced glyoxalase I activity mimics some changes associated with neurodegeneration, such as neurite retraction and apoptotic cell death. (c) 2006 Wiley-Liss, Inc.
引用
收藏
页码:1591 / 1600
页数:10
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