Phosphorylation sensitizes microtubule-associated protein τ to Al3+-induced aggregation

In Alzheimer's disease the microtubule- associated protein tau becomes hyperphosphorylated and aggregates into paired helical filaments (PHFs). Although the biochemical basis of the aggregation of tau into PHFs is not very clear, Al3+ has been suggested to play some role. Previous studies have shown that Al3+ alters the phosphorylation state and causes aggregation of tau in experimental animals and cultured neurons. In this study Al3+ inhibited phosphorylation of tau by neuronal cdc2-like kinase and dephosphorylation of phosphorylated tau by phosphatase 2B. These inhibitions are very likely due to Al3+-induced aggregations of various proteins present in phosphorylation/dephosphorylation assay mixtures since Al3+ caused aggregations of all proteins examined. Furthermore, compared to other proteins, tau displayed only an average sensitivity towards Al3+-induced aggregation. However upon phosphorylation, tau's sensitivity towards Al3+ increased 3.5 fold. In the presence of the metal chelator EDTA, Al3+-induced aggregates of tau became soluble, whereas Al3+-induced phosphorylated tau aggregates were insoluble in the buffer containing EDTA and remained insensitive to proteolysis. Our data suggest that phosphorylation sensitizes tau to Al3+ and phosphorylated tau transforms irreversibly into a phosphatase and protease resistant aggregate in presence of this metal ion.