Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments

One of the hallmarks of Alzheimer's disease is the abnormal state of the mi crotubule-associated protein tau in neurons. It is both highly phosphorylat ed and aggregated into paired helical filaments, and it is commonly assumed that the hyperphosphorylation of tan causes its detachment from microtubul es and promotes its assembly into PHFs. We have studied the relationship be tween the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. The proline-directed kinases MAPK and GSK3 are known to phosphorylate most Ser-Pro or Thr-Pro motifs in the regions flank ing the repeat domain of tau: they induce the reaction with several antibod ies diagnostic of Alzheimer PHFs, but this type of phosphorylation has only a weak effect on tau-microtubule interactions and on PHF assembly. By cont rast, MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addi tion PKA phosphorylates some sites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau's affinity for microtubu les, and at the same time inhibits tau's assembly into PHFs. Thus, contrary to expectations, the phosphorylation that detaches tau from microtubules d oes not prime it for PHF assembly, but rather inhibits it. Likewise, althou gh the phosphorylation sites on Ser-Pro or Thr-Pro motifs are the most prom inent ones on Alzheimer PHFs (by antibody labeling), they are only weakly i nhibitory to PHF assembly. This implies that the hyperphosphorylation of ta u in Alzheimer's disease is not directly responsible for the pathological a ggregation into PHFs; on the contrary, phosphorylation protects tau against aggregation.