Interaction of metal ions with tau protein. The case for a metal-mediated tau aggregation

Tau protein aggregation and its hyperphosphorylation play an important role in the pathogenesis of Alzheimer's disease. There is also considerable evidence for the accumulation of Fe2/3+, Cu2+, and Zn2+ in the brain of Alzheimer's patients, although their involvement in the etiology of the disease remains unknown. Here, interactions of the 3d metal ions Fe2/3+, Cu2+, and Zn2+ with the longest isoform of the human tau protein (htau40) are studied in detail. Electrospray mass spectrometry and ion mobility mass spectrometry analyses confirm the interactions of metal species with tau and that these interactions cause structural changes. Phosphorylation of the full-length htau40 with glycogen synthase kinase 3 beta (GSK3 beta), a protein kinase, causes a reduction in metal interactions. Transmission electron microscopy studies of the tau aggregates formed in the presence of metal ions suggest that the presence of metal ions influences the aggregation process. Fluorescence studies of full-length htau40 in the presence of Cu2+ indicate the formation of reactive oxygen species, which may contribute further to oxidative stress and neuronal death.