Abstract
BackgroundThe 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.MethodsWe 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.ResultsIn 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/2047-9158-3-24) contains supplementary material, which is available to authorized users.
Highlights
The transition metal copper enhances amyloid β aggregation and neurotoxicity, and in models of concomitant amyloid and tau pathology, copper promotes tau aggregation
Copper enhances tau phosphorylation independent of amyloid β (Aβ) in neuroblastoma cells Based upon previously published results [4,17], we sought to determine if copper was able to induce tau phosphorylation in the absence of Aβ, indicating a potential direct and independent effect
Cells incubated in the presence of 400 uM copper for 24 hours had higher amounts of phosphorylated tau at an Alzheimer’s disease (AD) relevant site as compared to the cells incubated in the absence of copper (Figure 1)
Summary
The transition metal copper enhances amyloid β aggregation and neurotoxicity, and in models of concomitant amyloid and tau pathology, copper promotes tau aggregation. We recently published results utilizing the Tg2576 mouse model and the systemic copper lowering therapy, zinc acetate [17] This treatment works by induced expression of metallothionein, resulting in a Cu-metallothionein complex which prevents uptake of copper in the gut. In our study we found that independent of genotype, oral zinc acetate administration was able to reduce both blood and brain copper levels while not affecting brain zinc levels [17] This resulted in decreased brain and blood copper, and reduced Aβ insolubility in a prevention paradigm, but not a treatment paradigm. Another group has examined the use of zinc sulfate in the 3×Tg mouse model and observed decreased Aβ and tau phosphorylation [19]. Whether the effect of copper on tau phosphorylation is independent of the Aβ/copper interaction is yet to be determined
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