57-59 Prevention of tau pathology has begun to emerge as a viable approach to prevention of neurodegeneration, although efforts in this area lag significantly behind the

anti-amyloid research. There are currently two major approaches in this area: i) prevention of tau aggregation; and ii) inhibition of tau phosphorylation. Prevention of tau aggregation The major function of tau in neurons is thought to be the stabilization of microtubles, and tau can be demonstrated Inhibitors,research,lifescience,medical to both increase the rate of assembly of tubulin into microtubules and stabilize existing microtubules.60 This activity appears to be controlled by phosphorylation of tau, in that phosphorylation of

tau renders it less efficient in promoting assembly, and is believed to dissociate tau from assembled microtubules. Tau is ordinarily a soluble protein, but forms insoluble, filamentous aggregates in the Inhibitors,research,lifescience,medical course of neurofibrillary tangle formation. Early-methods for purification of tangles took advantage of this insolubility, and employed harsh detergent and acid extraction techniques to dissolve away contaminating proteins.61,62 Both toxic gain of function and loss of function models have been PRT062607 manufacturer proposed for tau’s role Inhibitors,research,lifescience,medical in neuronal degeneration. The formation of tau aggregates may be toxic to neurons,63 or

conversely, conversion of tau into insoluble polymers Inhibitors,research,lifescience,medical may reduce the effectiveness of tau in stabilizing microtubules. It is still too early in this research to decide which model is more plausible. The mechanisms responsible for the conversion of a normally soluble monomeric protein into the insoluble filamentous aggregates have been the subject of intense study and the target for some drug development. Although tau in neurofibrillary tangles is hyperphosphorylated (see Inhibitors,research,lifescience,medical below),64 there is still much debate about the role of phosphorylation in aggregation of tau. Indeed, many of the studies of tau aggregation have shown the formation of filamentous aggregates from nonphosphorylated tau,65,66 and have the used such systems to screen for potential inhibitors of tau aggregation. These studies usually include polyanions such as heparin, RNA,65 or arachidonic acid67 to stimulate tau aggregation. Using such a system, unpublished results apparently revealed that methylene blue could inhibit tau aggregation, and this compound, under the name Rember, has been reported to be effective in preventing decline in clinical test scores in patients with Alzheimer’s disease.