Modulation of tau phosphorylation by environmental copper
Open accessAbstract
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.
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Copper can bind to tau in vitro and enhance tau phosphorylation by activating CDK5/P25 in AD transgenic mice.
“Copper can bind to tau in vitro [542, 543], and enhance tau phosphorylation by activating CDK5/P25 in AD transgenic mice (APPswe, PS1, P301Ltau) [544, 545].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [545]
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Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
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- Authors
- Voss, K., Harris, C., Ralle, M., Duffy, M., Murchison, C., & Quinn, J. F.
- Affiliations
- Oregon Health & Science University (US)
- Corresponding author
- Quinn, Joseph F
- Venue
- Translational Neurodegeneration
- Published
- 2014-11-17
- Volume
- 3
- Issue
- 1
- Pages
- 24-24
- ISSN
- 2047-9158 (ISSN-L)
- PMC
- PMC4322670
- OpenAlex
- W2146602519
- Cited by
- 83
- References
- 36
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 10 · 2023: 10 · 2022: 7 · 2021: 5 · 2020: 12 · 2019: 8 · 2018: 4 · 2017: 4 · 2016: 1 · 2015: 3
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Translational Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002113)
- National Institutes of Health (1s10rr025512-01)
- National Institute on Aging (T32AG023477)
- National Institute of Neurological Disorders and Stroke (U10NS077350)
- National Center for Research Resources (S10-RR025512)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Aluminum toxicity and tolerance in plants and animals
- Keywords
- tau phosphorylation, copper overload, zinc acetate, tetrathiomolybdate, Alzheimer's disease, tau pathology, amyloid-beta, neuroblastoma cells, novel object recognition, transgenic mouse model
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