, 2010). In SAHA HDAC research buy addition, acetylation of the 6 amino acid motif VQIINK (PHF6∗) inhibits the binding of tau to microtubules and enhances tau aggregation (Cohen et al., 2011). This motif is critical for the formation of tau oligomers and filaments (Sahara et al., 2007a and von Bergen et al., 2001). Thus, the combination of a tau acetylation inhibitor and a ubiquitination-proteasome enhancer might synergize to lower the level of pathogenic

tau species. Larger aggregates of tau are not likely to be accessible to the proteasome but can be degraded by the lysosomal pathway, in which autophagosomes engulf the aggregates and fuse with lysosomes. In cells overexpressing the microtubule repeat domain of tau with a deletion of K280, aggregated tau is removed by the lysosomal pathway (Wang et al., 2009). In slice culture, inhibition of the lysosomal pathway produces NFT-like tau deposition (Bi et al., 1999). The lysosomal pathway of tau degradation is also involved in Niemann-Pick type C (NPC) disease, an autosomal recessive disorder associated

with neurological symptoms and NFT formation in the brain (Auer et al., 1995). NPC disease is caused by a loss of function of NPC1, a lysosomal trafficking protein (Pacheco and Lieberman, 2008), suggesting that tau is degraded in lysosomes and that lysosomal dysfunction leads to tau accumulation. Consistent with this notion, phosphorylated tau Hormones antagonist is increased in the brains of NPC1-deficient mice and of NPC patients

(Bu et al., 2002). However, crossbreeding of NPC1-deficient mice with tau knockout mice mafosfamide worsened the phenotype (Pacheco et al., 2009), suggesting that the role of tau in this disease is complex. The autophagic-lysosomal pathway has also been interrogated in a Park2-deficient tauopathy model with parkinsonism overexpressing mutant human 4R2N tau under the mouse Thy1 promoter (PK−/−/TauVLW) (Rodríguez-Navarro et al., 2010). Treatment of 3-month-old PK−/−/TauVLW mice with trehalose, an mTOR-independent autophagy activator, for 2.5 months prevented dopaminergic neuron loss in the ventral midbrain, reduced phosphorylated tau and total tau in the striatum and limbic system, prevented brain astrogliosis, and improved motor and cognitive behavior. Biochemical and electron microscopy data suggested that the protective effects of trehalose were mediated, at least in part, by autophagy activation (Rodríguez-Navarro et al., 2010). Tau degradation can also be enhanced by specific activation of the immune system. Active immunization targeting phosphorylated tau reduced filamentous tau inclusions and neuronal dysfunction in transgenic mice overexpressing K257T/P301S human 4R0N tau under the rat tau promoter or P301L human 4R0N tau (JNPL3 model) (Asuni et al., 2007 and Boimel et al., 2010).