Modulación funcional de la Ca2+-ATPasa de membrana plasmática (PCMA) por tau, un marcador molecular clave en la enfermedad de Alzheimer

Abstract

The failure of neurons to keep optimal cytosolic Ca2+ concentration is a common feature of neurodegeneration by aging and aging-linked neuropathologies, such as Alzheimer´s disease (AD). However, the mechanisms that lead to this dysregulation are far from clear. One of the main hallmarks of AD is the microtubule associated protein tau, which forms neurofibrillary tangles that are toxic to cells. Tau has been linked to altered Ca2+ homeostasis, but the molecular mechanisms underlying this association are far from clear. The aim of this work is to study the functional relationship of tau with the accumulation of cytosolic Ca2+ through its interaction with Ca2+-ATPases, because these proteins have a key role in the fine tuning of Ca2+ concentrations in the cell. This thesis shows that tau inhibits specifically the activity of the plasma membrane Ca2+-ATPase (PMCA), being this effect dependent on the ionic nature of membrane lipids. The inhibitory effect of tau is aging and neurodegeneration dependent. Interaction and kinetic assays with truncated versions of PMCA have shown that tau binds to the C-terminal domain of PMCA. Calmodulin and methylene blue activate the PMCA and block and even reverse the inhibitory effect of tau. Taken together, the results of this thesis allow us (i) to propose PMCA as a target in the dysregulation of cytosolic calcium associated with neurodegeneration due to its functional interaction with tau, and (ii) that calmodulin and methylene blue counteract this inhibition and may therefore be relevant as possible therapeutic agents for AD and other tauopathies.