Tau phosphorylation and aggregation

The two most noticeable changes of Alzheimer tau are its aggregation and extensive phosphorylation. Therefore, it is of great interest to test how these properties are related, and in particular, whether the phosphorylation of tau promotes the aggregation. The issue has been addressed by various authors using tau phosphorylated by different kinases and/or using pseudophosphorylated forms of tau, where certain residues were exchanged for glutamate (for review, Stoothoff and Johnson 2005). In our opinion, these studies have yielded mixed results, i.e., the reported changes in aggregation kinetics caused by phosphorylation were, on the whole, quite variable. This variability is perhaps not surprising, considering the large number of potential phosphorylation sites on tau, the limited specificity of kinase preparations and the heterogeneity of phosphorylation states. In the case of some sites, e.g., the phosphorylation of the KXGS motifs in the repeat domain, phosporylation clearly inhibits aggregation rather than promoting it (Schneider et al. 1999). In the context of the present discussion, the important point is that aggregation of tau into bona fide PHFs can be achieved without any phosphorylation; therefore, it seems unlikely that phosphorylation has a major influence on PHF structure as such.

We also note that phosphorylation of tau in cells can change its properties on at least two different levels, tau-microtubule interactions and tau-tau interactions in PHFs. In the former case, phosphorylation generally tends to decrease the binding to microtubules (here again the phosphorylation at the KXGS motifs in the repeats and at S214 appear to have the most pronounced effects; Biernat et al. 1993; Brandt et al. 1994). The result is a decrease in microtubule stability but, perhaps more importantly, an increase in the cytosolic pool of tau, which can contribute to aggregation by mass action, independently of phosphorylation.

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