This latter observation also verifies that we do monitor the enzymatic reaction catalysed by PP2AT55a and not a spontaneous dephosphorylation under our NMR conditions. In addition to the fast dephosphorylation observed for pT153 and pT205 with the phosphate almost completely removed by 3.5 units of PP2AT55a after the first two spectra, two additional classes of residues could be distinguished. The first one contains pT231 and pS404, and is characterized by very slow kinetics with only a WWL229 marginal reduction of the phospho-resonance after one night. The second group shows intermediate dephosphorylation kinetics, and concerns pS199, pS202 and pS235. Tau phosphorylation is a reversible process that regulates in a complex manner its physiological role of microtubule stabilization. It is also linked to its pathological role, as the neurofibrillary tangles found inside the neurons of AD patients invariably contain a hyperSR-58611A phosphorylated form of Tau. Analysis with specific antibodies have shown that the latter form is characterized by the simultaneous presence of multiple phosphorylated residues, including the S202/T205 and T231 positions that constitute respectively the AT8 and AT180 epitopes. These phosphorylation events seemingly follow a hierarchical appearance, T231 being one of the earliest sites to be phosphorylated in AD brain before the epitope recognized by the AT8 antibody,. In the axon, PP2AT55a is associated with the microtubules, and its phosphatase activity counteracts the appearance of this multiply phosphorylated Tau. In addition, it has recently been reported that other neuronal PP2A heterotrimers might indirectly contribute to Tau phosphorylation/dephosphorylation by regulating the activities of GSK3b and CDK5 kinases. However, at a certain stage of the disease, this kinase-phosphatase balance breaks down, and one does observe the accumulation of hyperphosphorylated Tau in the somato-dendritic compartment. In this report, we investigate at the molecular level the enzymatic dephosphorylation of Tau by PP2AT55a, the major brain isoform of PP2A directly associated to microtubules and Tau, and ask whether certain phosphorylation events on Tau might exert an effect towards its activity at other sites.