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Methylglyoxal Induces Tau Hyperphosphorylation via Promoting AGEs Formation

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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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Acknowledgments

This work was supported by the National Nature Scientific Fund of China (No: 81171196).

Conflict of interest

There are no actual or potential conflicts of interest including any financial, personal, or other relationships with other people or organizations within three years of beginning the work submitted that could inappropriately influence (bias) our work.

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Authors and Affiliations

  1. 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

    Xiao-Hong Li, Jia-Zhao Xie, Xia Jiang, Bing-Ling Lv, Xiang-Shu Cheng, Lai-Ling Du, Jia-Yu Zhang, Jian-Zhi Wang & Xin-Wen Zhou

  2. Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital, Logistics College of Chinese People’s Armed Police Forces, Tianjin, 300162, China

    Xiao-Hong Li

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  1. Xiao-Hong Li
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Li, XH., Xie, JZ., Jiang, X. et al. Methylglyoxal Induces Tau Hyperphosphorylation via Promoting AGEs Formation. Neuromol Med 14, 338–348 (2012). https://doi.org/10.1007/s12017-012-8191-0

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