Cited by 123Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchProtein Kinase Regulation and GTPase Signaling

Zinc induces protein phosphatase 2A inactivation and tau hyperphosphorylation through Src dependent PP2A (tyrosine 307) phosphorylation

Xiong, Yan, Jing, Xiao-Peng, Zhou, Xin-Wen, Wang, Xiu-Lian, Yang, Yang, Sun, Xu-Ying, Qiu, Mei, Cao, Fu-Yuan +3 more·2013·Neurobiology of Aging

Abstract

The activity of protein phosphatase (PP) 2A is downregulated and promotes the hyperphosphorylation of tau in the brains of Alzheimer's disease (AD), but the mechanism for PP2A inactivation has not been elucidated. We have reported that PP2A phosphorylation at tyrosine 307 (Y307) is involved in PP2A inactivation. Here, we further studied the upstream mechanisms for PP2A phosphorylation and inactivation. We found that zinc, a heavy metal ion that is widely distributed in the normal brain and accumulated in the susceptible regions of AD brain, could induce PP2A inhibition, phosphorylation of PP2A at Y307 and tau hyperphosphorylation both in rat brains and cultured N2a cells, while zinc chelating prevented these changes completely. Upregulation of PP2A chemically or genetically attenuated zinc-induced tau hyperphosphorylation, whereas mutation of Y307 to phenylalanine abolished the zinc-induced tyrosine phosphorylation and inactivation of PP2A. Zinc could activate Src, while PP2, a specific Src family kinases inhibitor, attenuated zinc-induced PP2A phosphorylation and inactivation, indicating that zinc induces PP2A Y307 phosphorylation and inactivation through Src activation. In human tau transgenic mice, zinc chelator rescued PP2A activity, prevented Src activation, and reduced hyperphosphorylated and insoluble tau levels. We concluded that zinc induces PP2A inactivation and tau hyperphosphorylation through Src-dependent pathway, regulation of zinc homeostasis may be a promising therapeutic for AD and the related tauopathies.

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Crossref · 10.1016/j.neurobiolaging.2012.07.003

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Authors
Xiong, Y., Jing, X.-P., Zhou, X.-W., Wang, X.-L., Yang, Y., Sun, X.-Y., Qiu, M., Cao, F.-Y., Lu, Y.-M., Liu, R., & Wang, J.-Z.
Affiliations
Huazhong University of Science and Technology (CN)
Corresponding author
  • Liu, Rong
  • Wang, Jian-Zhi
Venue
Neurobiology of Aging
Publisher
Elsevier BV
Published
2013-03
Volume
34
Issue
3
Pages
745-756
ISSN
0197-4580 (ISSN-L)
OpenAlex
W2149203347
Cited by
122
References
57
Citations by year
2026: 5 · 2025: 1 · 2024: 7 · 2023: 10 · 2022: 10 · 2021: 14 · 2020: 14 · 2019: 8 · 2018: 9 · 2017: 9 · 2016: 9 · 2015: 9 · 2014: 11 · 2013: 6
FWCI
5.58
Type
journal article
Language
en
Open access
closed
Locations
  • Neurobiology of Aging (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (91132305, 81171196)
  • Fundamental Research Funds for the Central Universities (2010MS050, 2012QN133)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
zinc, protein phosphatase 2A, tau hyperphosphorylation, Src family kinases, Alzheimer's disease, zinc chelation, zinc homeostasis, tauopathy
MeSH terms
Animals, Brain, Humans, Mice, Transgenic, Neurons, Phosphorylation, Pyrimidines, Trace Elements, Tyrosine, Zinc, tau Proteins, Rats, Sprague-Dawley, src-Family Kinases, Tauopathies, Cell Line, Tumor, Mice, Rats, Protein Phosphatase 2

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