Modulation of tau phosphorylation by environmental copper

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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
Volume3
Issue number1
DOIs
StatePublished - Nov 17 2014

Fingerprint

Copper
Phosphorylation
Amyloid
Zinc Acetate
Pathology
Brain
Metals
Insurance Benefits
Neuroblastoma
Transgenic Mice
Zinc
Mass Spectrometry
Alzheimer Disease
Cell Culture Techniques
Western Blotting
Diet

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Cognitive Neuroscience

Cite this

Modulation of tau phosphorylation by environmental copper. / Voss, Kellen; Harris, Christopher; Ralle, Martina; Duffy, Megan; Murchison, Charles; Quinn, Joseph.

In: Translational Neurodegeneration, Vol. 3, No. 1, 24, 17.11.2014.

Research output: Contribution to journalArticle

Voss, Kellen ; Harris, Christopher ; Ralle, Martina ; Duffy, Megan ; Murchison, Charles ; Quinn, Joseph. / Modulation of tau phosphorylation by environmental copper. In: Translational Neurodegeneration. 2014 ; Vol. 3, No. 1.
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