Neurodegenerative tauopathies encompass a large group of neurodegenerative disorders, including Alzheimer’s disease (AD), that are characterized by the formation of tau inclusions in selective brain regions (Lee et al., 2001). The precise etiology of AD is not known in detail, but pathologically, it is characterized by progressive accumulation of abnormally modified tau in neurofibrillary tangles (NFTs), as well as formation of amyloid plaques composed mainly of ß-amyloid peptides (Lee et al., 2001). In the normal brain, tau is a highly soluble protein with limited secondary structure that binds and stabilizes the microtubule network. In the diseased state, however, tau undergoes a series of posttranslational modifications that include phosphorylation (recognized by the AT8-and TG3-specific tau antibodies), abnormal conformations (MC1-or Alz-50-positive), and truncation events that lead to the formation of highly insoluble aggregates positive for Thioflavin S and resistant to proteinase K activity (Binder et al., 2005). Specifically, truncation events at the N-and C-terminal regions promote the formation of tau fragments composed mainly of the microtubule binding repeat region (MTBR) that is responsible for the aggregation and propagation of tau pathology (Binder et al., 2005; Frost et al., 2009). In the AD brain, tau aggregates develop in a stereotypical pattern, first appearing in the transentorhinal cortex, and then spreading to the hippocampus and finally to neocortical regions (Braak and Braak, 1996). To mimic the progression of tau pathology of human AD, animal models, in which the expression of human tau harboring the P301L mutation associated with frontal temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is restricted to the entorhinal cortex, have been generated (Liu et al., 2012; de Calignon et al., 2012). In these models, mutant tau spreads from the entorhinal cortex to interconnected hippocampal and cortical structures over time, suggesting tau aggregates propagate transsynaptically, similar to what occurs in human AD brains (Liu et al., 2012; de Calignon et al., 2012). Notably, mutant human tau recruited and coaggregated with endogenous murine tau, even in brain areas devoid of human tau expression, indicating that abnormal human tau serves as a seed to induce and propagate murine tau aggregation (de Calignon et al., 2012). Severalin vitrostudies have shown that synthetic tau aggregates composed of specific tau isoforms can be taken up by cells and induce aggregation of endogenously expressed tau, a pathological process that can propagate between cells (Frost et al., 2009). To determine whether the tau pathology can propagate in vivo, Clavaguera et al.(2009) injected mouse brain lysates containing insoluble human tau proteins harboring the P301S mutation (associated with FTDP-17 and known to promote aggregation similar to P301L-tau) into brains of nonsymptomatic mice expressing human wild-type tau. Tau pathology developed at the injection site and then spread to neighboring brain regions, suggesting that insoluble brain lysates containing mutant tau proteins promote the spatial transmission of tau pathology (Clavaguera et al., 2009). A recent article published in The Journal of Neuroscience investigated this topic further. To determine whether recombinant mutant (P301S) full-length or truncated (containing only the MTBR domain) tau preformed fibrils (pffs) generated in vitro also induce tau pathology in vivo, Iba et al.(2013) injected tau pffs unilaterally in young presymptomatic mice expressing human P301S-mutated tau. Tau pffs accelerated the formation of tau inclusions in young mice: inclusions …