Modifications of tau protein during neuronal cell death

Accumulation of hyperphosphorylated tau protein and progressive neuronal loss are among the major hallmarks of certain neurodegenerative disorders including Alzheimer's disease. However, the relationship between tau phosphorylation and neuronal cell death remains unclear. Here we have analyzed tau modifications during two forms of neuronal death, apoptosis and necrosis, using primary cultures of cerebellar granule neurons as a simple model system. Induction of neuronal apoptosis by inhibition of phosphatidylinositol 3-kinase results in a rapid increase in the phosphorylation of tau, which is followed by the dephosphorylation and cleavage of the protein. In contrast, necrosis triggered by high salt shock or glutamate treatment leads to a rapid dephosphorylation and an almost complete proteolysis of tau. These data suggests that a transient tau hyperphosphorylation occurs at an early stage of apoptosis, whereas tau is dephosphorylated and cleaved during the late phase of apoptosis as well as in necrotic neurons.