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

Yan Xiong1, Xiao-Peng Jing, Xin-Wen Zhou

  • 1Department of Pathophysiology, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China.

Neurobiology of Aging
|August 16, 2012
PubMed

Insights

Zinc accumulation inactivates protein phosphatase 2A (PP2A) by activating Src kinases, leading to tau hyperphosphorylation in Alzheimer's disease (AD). Targeting zinc may offer a new therapeutic strategy for AD and tauopathies.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pathology

Background:

  • Protein phosphatase 2A (PP2A) activity is reduced in Alzheimer's disease (AD), correlating with tau hyperphosphorylation.
  • PP2A inactivation is linked to its phosphorylation at tyrosine 307 (Y307), but upstream mechanisms remain unclear.

Purpose of the Study:

  • To investigate the role of zinc in PP2A inactivation and tau hyperphosphorylation.
  • To elucidate the signaling pathway mediating zinc-induced PP2A dysfunction.

Main Methods:

  • Experiments in rat brains and N2a cells using zinc exposure and chelation.
  • Genetic manipulation of PP2A (Y307 mutation, upregulation) and Src kinase inhibition.
  • Studies in human tau transgenic mice.

Main Results:

  • Zinc induced PP2A inhibition, Y307 phosphorylation, and tau hyperphosphorylation in vitro and in vivo.
  • Zinc activated Src kinases, which mediated PP2A Y307 phosphorylation and inactivation.
  • Zinc chelation in tau transgenic mice restored PP2A activity and reduced tau pathology.

Conclusions:

  • Zinc inactivates PP2A via a Src-dependent pathway, promoting tau hyperphosphorylation in AD.
  • Regulating zinc homeostasis presents a potential therapeutic avenue for AD and tauopathies.

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