Specifically, exposure to Cu with drinking water (0.13 ppm CuCl2) for 12 months in triple-transgenic 3xTg-AD mice characterized by three Alzheimer’s disease-specific mutations (APP Swedish, MAPT P301L, PSEN1 M146V), resulted in brain oxidative stress, synaptic dysfunction, Aβ accumulation, spatial memory impairment, as well as a significant disruption of both mitochondrial and nuclear proteome. Here, MAPT is linked to Alzheimer disease.