Other functions were revealed by analysis of tau knockout mice, but the precise mechanisms are poorly understood. A major advantage of tau knockout models is that they can reveal unique functions

of tau that are not redundant with the functions of other proteins. For example, tau reduction prevents behavioral deficits in several models of AD (see below), suggesting that unique functions of tau are important in the pathogenesis of this condition. It remains controversial whether animal models with high levels of tau overexpression can provide relevant insights into human conditions in which such overexpression does not occur. However, the accumulation and abnormal distribution of hyperphosphorylated and aggregated tau in these models does simulate key aspects of human tauopathies. Concerns may also Selleck MK2206 be raised about the relevance of studies investigating tau in nonneuronal cells. Although neurons are probably

the most relevant cell type to study in relation to tauopathies, some tauopathies are associated with tau pathology in glial cells (Higuchi et al., 2005), and the proteins that interact with tau in different cell types likely overlap. Tau has numerous binding partners http://www.selleckchem.com/products/bgj398-nvp-bgj398.html (Table 1), including signaling molecules, cytoskeletal elements and lipids, suggesting that it is a multifunctional protein. Indeed, tau can bind to and affect cytoskeletal EPHB3 components and regulate signaling pathways by acting as a protein scaffold for signaling complexes; tau binding also activates or inhibits several enzymes. The most extensively described activity of tau—binding to microtubules—occurs in vitro and in vivo. In fact, the majority of tau in the cell is bound to microtubules. In cell-free conditions, this microtubule binding activity promotes microtubule assembly and stability (Weingarten

et al., 1975). However, in cell culture, tau colocalizes with those microtubules that are most dynamic and most susceptible to drug-induced depolymerization (Kempf et al., 1996). Moreover, the population of tau-bound microtubules has the highest basal turnover rate of any microtubule population, both in rat primary neuronal culture and in mouse hippocampus in vivo (Fanara et al., 2010), raising doubts about the essential role of tau in microtubule stabilization postulated on the basis of in vitro findings. In addition, knockdown of tau by siRNA is not lethal to primary neurons in culture and does not decrease the number of microtubules or their polymerization state (King et al., 2006 and Qiang et al., 2006). Thus, microtubule stabilization may not be a critical function of tau in vivo. The in vivo functions of tau appear to overlap with those of MAP1B, another microtubule-associated protein found in axons.