MODIFICATION OF TAU TO AN ALZHEIMERS TYPE PROTEIN INTERFERES WITH ITSINTERACTION WITH MICROTUBULES

The microtubule associated protein tau is the main structural componen t of paired helical filaments (PHFs), aberrant polymers found intracel lularly in neurons of brains with the Alzheimers disease. Glycation is one of the posttranslational modifications that has been found in tau from PHFs, but not in normal brain tau. Studies were carried out with purified tau protein subjected to chemical modifications, in order to further investigate the mechanisms of tau self-association into PHFs. Tau was subjected to modifications affecting reactive lysyl residues, e.g., carbamoylation with potassium cyanate and glycation reaction wi th glucose. The effects of these modifications to produce functional a lterations in tau capacity to bind brain tubulin and to induce microtu bule assembly were investigated. Chemically-modified tau and tau of Al zheimer's type exhibited a similar microtubule interaction behavior as analysed by overlay assays, but those were different than normal tau controls. On the other hand, studies of the microtubule assembly kinet ics indicated that the reported tau modifications resulted in a loss o f its capacity to promote microtubule assembly from purified tubulin p reparations. The data on the differences in the electrophoretic profil es, Western blots and the overlay patterns, along with those on the mi crotubule polymerisation of normal brain tau as compared with both mod ified and Alzheimer's tau, suggest changes in the functional behavior of this protein as a result of its structural modifications. These stu dies were complemented with an immunogold analysis at the electron mic roscope level, which indicated that the modified tau did not incorpora te into assembled microtubules. These findings, combined with the resu lts on tau chemical modifications suggest that the reactive lysine res idues within functional domains on tau, e.g., those of the repetitive binding motifs, were affected by these modifications. Furthermore, the se observations provide new clues to understand the anomalous interact ions of tau in Alzheimer's disease.