We have previously observed that recombinant tau fibrils will induce aggregation of full-length intracellular tau in cultured cells and that aggregated forms of tau transfer between cells (Frost et al., 2009). Further, we found that intracellular tau fibrils are released free into the media, where they propagate aggregation by direct interaction

with native tau in recipient cells. An anti-tau antibody (HJ9.3) blocks this process by preventing Selleck Temsirolimus tau aggregate uptake into recipient cells (Kfoury et al., 2012). In addition to similar experiments with recombinant tau (Guo and Lee, 2011), others have shown that paired helical filaments from AD brain induce cytoplasmic tau aggregation (Santa-Maria et al., 2012). Injection of brain extract from human P301S

tau transgenic mice into the brains of mice expressing wild-type human tau induces assembly of wild-type human tau into filaments and spreading of pathology (Clavaguera et al., 2009). Similar effects occurred after injection of recombinant full-length or truncated tau fibrils, which caused rapid induction of NFT-like inclusions that propagated from injected sites to connected brain regions in a time-dependent manner (Iba et al., 2013). Selective tau expression in the entorhinal cortex caused late pathology in the axonal terminal zones in cells in the dentate gyrus and hippocampus, consistent with transsynaptic movement of aggregates (de Calignon et al.,

2012 and Liu et al., 2012). A growing body Talazoparib in vitro of work thus supports the idea that tau aggregates transfer between cells and might be targeted with therapeutic antibodies. In mouse models that mimic aspects of AD and Parkinson’s disease, passive immunization using antibodies against Aβ and alpha synuclein can reduce Aβ and alpha-synuclein deposition in brain (Bard et al., 2000, DeMattos et al., 2001 and Masliah et al., 2011) and improve behavioral deficits (Dodart et al., 2002, Kotilinek et al., 2002 and Masliah et al., 2011). Active immunization in tauopathy mouse models using tau phospho peptides reduced tau pathology (Bi et al., 2011 and Boimel et al., 2010) and in some studies improved behavioral deficits because (Asuni et al., 2007, Boutajangout et al., 2010 and Troquier et al., 2012). In two passive vaccination studies, there was reduced tau pathology and improved motor function when the antibody was given prior to the onset of pathology (Boutajangout et al., 2011 and Chai et al., 2011). While several of the tau immunization studies appear to show some beneficial effects, the maximal expected efficacy of anti-tau antibodies administered after the onset of pathology, the optimal tau species to target, and the mechanism of the therapeutic effect have remained unknown. Our prior work in cell culture has suggested that aggregate flux in and out of cells might be central to progressive pathology (Kfoury et al., 2012).