Functional studies of Alzheimer's disease tau protein.

In vitro assays were used to monitor and compare the kinetic behavior of bovine tubulin polymerization enhanced by tau proteins isolated from Alzheimer's disease (AD) and nondemented (ND) age-matched control brains. Tau from AD cases induced slower polymerization and a steady state turbidity value approximately 50% of that stimulated by tau from control cases. Tau from the most severe AD case was least effective at promoting polymerization. Dark-field light microscopy of the control samples revealed abundant microtubule formation and many microtubule bundles. Microtubule assembly was observed in AD samples as well, but bundling was not obvious. These results were confirmed by negative-stain electron microscopy. Morphological analysis showed that AD tau-induced microtubules were longer than control microtubules. Furthermore, our initial results suggest that the reduction of AD tau activity is correlated with neurofibrillary pathology in AD brains. Earlier reports indicated that AD tau is modified by phosphorylation (Grundke-Iqbal et al., 1986; Wood et al., 1986; Iqbal et al., 1989; Brion et al., 1991a,b; Lee et al., 1991). Our results support the hypothesis that tau modification compromises its function by altering its ability to nucleate and bundle microtubules.