TAU-SELF-ASSOCIATION - STABILIZATION WITH A CHEMICAL CROSS-LINKER ANDMODULATION BY PHOSPHORYLATION AND OXIDATION-STATE

tau is a major component of paired helical filaments found in the neur ofibrillary tangles of Alzheimer's diseased brain. However, the mechan ism or mechanisms responsible for the association of tau to form these aggregates remains unknown. In this study, the role of intermolecular disulfide bonds in the formation of higher order oligomers of bovine tau and the human recombinant tau isoform T3 was examined using the ch emical cross-linking agent disuccinimidylsuberate (DSS). In addition, the role of phosphorylation and oxidation state on the in vitro self-a ssociation of tau was studied using this experimental model. Stabiliza tion of tau-tau interactions with DSS indicated that intermolecular di sulfide bonds probably play a predominant role in dimer formation, but the formation of higher order oligomers of tau cannot be attributed t o these bonds alone. tau-tau interactions were significantly decreased either by blocking Cys residues or by exposing the tau to a reducing (nitrogen and dithiothreitol), instead of an oxidizing, environment. t au self-association was also significantly decreased by prior phosphor ylation with calcium/calmodulin-dependent protein kinase II. Phosphory lation by cyclic AMP-dependent protein kinase or dephosphorylation by alkaline phosphatase did not alter tau self-assembly. These data sugge st a role for several factors that may modulate tau self-association i n vivo.