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Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation.

Abstract

The hyperphosphorylated tau is a major protein component of neurofibrillary tangle, which is one of hallmarks of Alzheimer's disease (AD). While the level of methylglyoxal (MG) is significantly increased in the AD brains, the role of MG in tau phosphorylation is still not reported. Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE). Glycogen synthesis kinase-3β (GSK-3β) and p38 MAPK were activated, whereas the level and activity of JNK, Erk1/2, cdk5, and PP2A were not altered after MG treatment. Simultaneous inhibition of GSK-3β or p38 attenuated the MG-induced tau hyperphosphorylation. Aminoguanidine, a blocker of AGEs formation, could effectively reverse the MG-induced tau hyperphosphorylation. These data suggest that MG induces AD-like tau hyperphosphorylation through AGEs formation involving RAGE up-regulation and GSK-3β activation and p38 activation is also partially involved in MG-induced tau hyperphosphorylation. Thus, targeting MG may be a promising therapeutic strategy to prevent AD-like tau hyperphosphorylation.

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  • Authors+Show Affiliations

    ,

    Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

    , , , , , , ,

    Source

    Neuromolecular medicine 14:4 2012 Dec pg 338-48

    MeSH

    Alzheimer Disease
    Animals
    Cell Line, Tumor
    Enzyme Activation
    Glycation End Products, Advanced
    Glycogen Synthase Kinase 3
    Glycogen Synthase Kinase 3 beta
    Guanidines
    Mice
    Neuroblastoma
    Phosphorylation
    Protein Kinases
    Protein Processing, Post-Translational
    Pyruvaldehyde
    Receptor for Advanced Glycation End Products
    Receptors, Immunologic
    Up-Regulation
    p38 Mitogen-Activated Protein Kinases
    tau Proteins

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22798221

    Citation

    Li, Xiao-Hong, et al. "Methylglyoxal Induces Tau Hyperphosphorylation Via Promoting AGEs Formation." Neuromolecular Medicine, vol. 14, no. 4, 2012, pp. 338-48.
    Li XH, Xie JZ, Jiang X, et al. Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation. Neuromolecular Med. 2012;14(4):338-48.
    Li, X. H., Xie, J. Z., Jiang, X., Lv, B. L., Cheng, X. S., Du, L. L., ... Zhou, X. W. (2012). Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation. Neuromolecular Medicine, 14(4), pp. 338-48. doi:10.1007/s12017-012-8191-0.
    Li XH, et al. Methylglyoxal Induces Tau Hyperphosphorylation Via Promoting AGEs Formation. Neuromolecular Med. 2012;14(4):338-48. PubMed PMID: 22798221.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation. AU - Li,Xiao-Hong, AU - Xie,Jia-Zhao, AU - Jiang,Xia, AU - Lv,Bing-Ling, AU - Cheng,Xiang-Shu, AU - Du,Lai-Ling, AU - Zhang,Jia-Yu, AU - Wang,Jian-Zhi, AU - Zhou,Xin-Wen, Y1 - 2012/07/14/ PY - 2012/03/21/received PY - 2012/06/22/accepted PY - 2012/7/17/entrez PY - 2012/7/17/pubmed PY - 2013/5/8/medline SP - 338 EP - 48 JF - Neuromolecular medicine JO - Neuromolecular Med. VL - 14 IS - 4 N2 - The hyperphosphorylated tau is a major protein component of neurofibrillary tangle, which is one of hallmarks of Alzheimer's disease (AD). While the level of methylglyoxal (MG) is significantly increased in the AD brains, the role of MG in tau phosphorylation is still not reported. Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE). Glycogen synthesis kinase-3β (GSK-3β) and p38 MAPK were activated, whereas the level and activity of JNK, Erk1/2, cdk5, and PP2A were not altered after MG treatment. Simultaneous inhibition of GSK-3β or p38 attenuated the MG-induced tau hyperphosphorylation. Aminoguanidine, a blocker of AGEs formation, could effectively reverse the MG-induced tau hyperphosphorylation. These data suggest that MG induces AD-like tau hyperphosphorylation through AGEs formation involving RAGE up-regulation and GSK-3β activation and p38 activation is also partially involved in MG-induced tau hyperphosphorylation. Thus, targeting MG may be a promising therapeutic strategy to prevent AD-like tau hyperphosphorylation. SN - 1559-1174 UR - https://www.unboundmedicine.com/medline/citation/22798221/Methylglyoxal_induces_tau_hyperphosphorylation_via_promoting_AGEs_formation_ L2 - https://dx.doi.org/10.1007/s12017-012-8191-0 DB - PRIME DP - Unbound Medicine ER -