Modulation of tau phosphorylation by environmental copper

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Copper is known to enhance amyloid-beta aggregation and neurotoxicity.
• In models with both amyloid and tau pathology, copper also promotes tau aggregation.
• The current study investigates copper's effect on tau pathology independently of amyloid-beta.

Purpose of the Study:

• To determine if environmental copper affects tau pathology in the absence of pathological amyloid-beta.
• To assess the impact of copper overload and copper complexing on tau phosphorylation.
• To evaluate the potential of copper reduction as a therapeutic strategy for Alzheimer's disease.

Main Methods:

• Utilized cell culture and transgenic murine models to examine copper's effect on tau phosphorylation.
• Administered oral zinc acetate to mice as a copper-lowering agent.
• Measured blood and brain metal levels using inductively coupled plasma mass spectroscopy.
• Assessed behavioral changes using the Morris water maze and novel object recognition tasks.
• Analyzed tau phosphorylation levels via Western blots with phosphorylation-specific antibodies.

Main Results:

• Excess copper increased tau phosphorylation in human neuroblastoma cells.
• A copper-complexing agent, tetrathiomolybdate, reduced tau phosphorylation in cell cultures.
• Oral zinc acetate lowered copper levels in mouse plasma and brain.
• Copper reduction in mice significantly attenuated tau phosphorylation.
• No significant behavioral changes were observed, though a trend towards improved novel object recognition was noted.

Conclusions:

• Reducing brain copper by limiting dietary intake may be a viable strategy for managing tau pathology in Alzheimer's disease.
• The potential benefits are moderated by the lack of observed behavioral improvements and risks associated with excessive copper reduction.