Tau phosphorylation in hippocampus results in toxic gain-of-function

The MAP (microtubule-associated protein) tau binds to tubulin, the main component of MTs (microtubules), which results in the stabilization of MT polymers. Tau binds to the C-terminal of tubulin, like other MAPs (including motor proteins such as kinesin) and it therefore may compete with these proteins for the same binding site in the tubulin molecule. In pathological conditions, tau is the main component of aberrant protein aggregates found in neurodegenerative disorders known as tauopathies where tau is present in its hyperphosphorylated form. GSK3 (glycogen synthase kinase 3, also known as tau kinase I) has been described as one of the main kinases involved in tau modifications. We have analysed the role of phospho-tau as a neurotoxic agent. We have analysed a transgenic mouse model which overexpresses GSK3beta. In this transgenic mouse, a clear degeneration of the dentate gyrus, which increases with age, was found. In a double transgenic mouse, which overexpresses GSK3 and tau at the same time, dentate gyrus degeneration was dramatically increased. This result may suggest that phospho-tau may be toxic inside neurons of the dentate gyrus. Once neuronal degeneration takes place, intracellular tau is secreted to the extracellular space. The present review discusses the toxicity of this extracellular tau for surrounding neurons.