Modulation of tau phosphorylation by environmental copper

Kellen Voss, Christopher Harris, Martina Ralle, Megan Duffy, Charles Murchison, Joseph F. Quinn

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Background: The transition metal copper enhances amyloid β aggregation and neurotoxicity, and in models of concomitant amyloid and tau pathology, copper also promotes tau aggregation. Since it is not clear if the effects of environmental copper upon tau pathology are dependent on the presence of pathological amyloid β, we tested the effects of copper overload and complexing in disease models which lack pathological amyloid β. Methods: We used cell culture and transgenic murine models to test the effects of environmental copper on tau phosphorylation. We used oral zinc acetate as a copper lowering agent in mice and examined changes in blood and brain metals through inductively coupled plasma mass spectroscopy. Behavioral effects of copper lowering were assessed with Morris water maze and novel object recognition tasks. Changes in tau phosphorylation were examined by phosphorylation specific antibodies on Western blots. Results: In human neuroblastoma cells, excess copper promoted tau phosphorylation and a copper complexing agent, tetrathiomolybdate, attenuated tau phosphorylation. In a transgenic mouse model expressing wild type human tau, copper-lowering by oral zinc suppressed plasma and brain levels of copper, and resulted in a marked attenuation of tau phosphorylation. No significant changes in behavior were observed with copper lowering, but a trend to improved recognition of the novel object was observed in zinc acetate treated mice. Conclusions: We propose that reduction of brain copper by blocking uptake of copper from the diet may be a viable strategy for modulating tau pathology in Alzheimer's disease. The potential benefits of this approach are tempered by the absence of a behavioral benefit and by the health risks of excessive lowering of copper.

Original languageEnglish (US)
Article number24
JournalTranslational Neurodegeneration
Issue number1
StatePublished - Nov 17 2014


  • Alzheimer's disease
  • Copper
  • Tau protein
  • Transgenic mice

ASJC Scopus subject areas

  • Clinical Neurology
  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience


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