P4–035: Egb761 reduces zinc‐induced tau phosphorylation at Ser262 in rat primary cortical neurons

Background: The aggregation of proteins, such as tau, that occurs in neurodegenerative diseases is classically thought to occur as an undesirable, nonfunctional byproduct of protein misfolding. In contrast, RNA binding proteins use protein aggregation as part of a normal regulated, physiological mechanism that consolidates RNA-protein complexes. RNA binding proteins play fundamental roles in managing RNA splicing, transport and translation. The complexes of RNA-protein aggregates have many different functions, but play a particularly prominent role during conditions of stress, where they form complexes termed stress granules. Methods: Using biochemical and immunochemical approaches, we investigated the process of aggregation of tau and TDP-43, which are two proteins that form intracellular aggregates. Studies were done using a range of systems, including neuronal cell culture, transgenic mice and human post-mortem specimens. Results:We observe that intracellular aggregates of tau and TDP-43 co-localize with numerous RNA binding proteins, including TIA-1, TTP and eIF3. The RNA binding protein complexes fulfilled criteria of stress granules, suggesting that they are linked to known physiological processes regulating RNA binding protein aggregation. The degree of co-localization varies with disease state and the type of RNA binding protein examined. Mice expressing APP alone (5xFAD) do not exhibit strong formation of stress granules. In contrast mice expressing APP and tau (3xTgAD) exhibit particularly strong co-localization between tau and RNA binding proteins. Our studies of tau protein indicate that some RNA binding proteins directly interact with tau in a manner that reflects tau phosphorylation. The interaction between tau and TIA-1 might have important effects on the tendency of tau to aggregate, because co-transfecting tau with TIA-1 induces hyperphosphorylated tau inclusions. Conclusions:We hypothesize that aggregation of RNA binding proteins contributes to the pathophysiology of tau in Alzheimer’s disease and other tauopathies. RNA granules, such as stress granules, protect against stress, but under conditions of chronic stress the process might become overactive producing pathological stress granules that persist and interfere with neuronal functions. RNA binding proteins might represent a previously "hidden" component of intracellular aggregates that can be utilized as diagnostic and/or therapeutic targets.