We have only tested three therapeutic antibodies in vivo. Thus, the correlations with the in vitro assays could be through

chance. Further studies of anti-tau antibodies with variable potencies in the seeding assay will help address this question. In addition, Fulvestrant datasheet correlation of antibody affinity, epitope, isotype, glycosylation, and ability to bind phosphorylated forms of tau will be important to assess in future studies. This study also reports the effects of direct, intra-CNS infusion of anti-tau antibodies. Despite the fact that the antibodies utilized each target different tau epitopes and do not target phospho-tau, two of three strongly reduced abnormal tau load both immunohistologically and biochemically, and two significantly improved memory, one to a greater extent than

the other. Effects on tau pathology also correlated very well with a reduction in intrinsic Smad tumor seeding activity. HJ8.5 and HJ9.3 strongly decreased pathological tau seeds in vivo. A strong reduction in tau pathology might occur by preventing induction of tau aggregation in neighboring cells. While HJ9.4 did not decrease pathology as potently, it did decrease tau pathology in the amygdala. The variation in effectiveness in different brain regions among the antibodies may be due to the formation of region-specific aggregate conformers for which the antibodies have subtle differences in binding affinity. Once extracellular tau aggregates are sequestered by anti-tau antibodies in vivo, their metabolic fate is not yet

clear. After 3 months of antibody administration, we found reduced microglial activation, presumably due to less tau-related pathology and neurodegeneration. Several months of passive immunization with anti-Aβ antibodies has also been noted to reduce microgliosis (Wilcock et al., 2003). The mechanism by which antibody/tau complexes are cleared in vivo, and the mechanism via which they decrease tau pathology, remains to be definitively clarified. It has been suggested that immunization with anti-α-synuclein antibodies clears α-synuclein aggregates by promoting lysosomal these degradation (Masliah et al., 2011). A recent study with anti-α-synuclein antibodies showed that the antibodies targeted α-synuclein clearance mainly via microglia, presumably through Fc receptors (Bae et al., 2012). Neurons express Fcγ receptors (Andoh and Kuraishi, 2004 and Mohamed et al., 2002) and may be able to internalize IgG complexed with antigen by high-affinity FcγRI receptor (Ravetch and Bolland, 2001). Internalized tau antibodies may contact tau in endosomes and eventually induce clearance of intracellular tau aggregates by the endosomal/lysosomal system (Sigurdsson, 2009). Though the anti-tau antibodies used in our current study can bind extracellular tau assemblies, we found no evidence of significant localization within cells.