Ca 2+ -ATPases are plasma membrane and intracellular membrane transporters that use the energy of ATP hydrolysis to pump cytosolic Ca 2+ out of the cell (PMCA) or into internal stores. These pumps are the main high-affinity Ca 2+ systems involved in the maintenance of intracellular free Ca 2+ at the properly low level in eukaryotic cells. The failure of neurons to keep optimal intracellular Ca 2+ concentrations is a common feature of neurodegeneration by aging and aging-linked neuropathologies, such as Alzheimer's disease (AD). This disease is characterized by the accumulation of β-amyloid senile plaques and neurofibrillary tangles of tau, a protein that plays a key role in axonal transport. Here we show a novel inhibition of PMCA activity by tau which is concentration-dependent. The extent of inhibition significantly decreases with aging in mice and control human brain membranes, but inhibition profiles were similar in AD-affected brain membrane preparations, independently of age. No significant changes in PMCA expression and localization with aging or neuropathology were found. These results point out a link between Ca 2+ -transporters, aging and neurodegeneration mediated by tau protein.