T neocortical areas (Bancher et al. 1993). Recently, the interneuronal transmission of tau pathology was reported in vitro whereby exogenously added tau fibrils were internalized into host cells and induced the aggregation of endogenous tau protein (Frost et al. 2009; Guo and Lee 2011). In addition, tau aggregates have been shown to be transferred between cells in a co-culture systemCell Tissue Res (2013) 352:33(Clavaguera et al. 2009). Similar results have been obtained in vivo in mice that express a human wild-type tau transgene and that do not develop tau filaments under normal conditions (Clavaguera et al. 2009). Here, the intracerebral injection of brain extracts derived from mutant P301S tau transgenic mice leads to the aggregation of wild-type human tau in host mice. The seeding capacity is dependent on the solubility of the tau aggregates. Insoluble tau fractions possess a much higher seeding capacity compared with soluble fractions. Interestingly, upon injection of tau aggregates into non-transgenic wild-type mice, aggregates have been confirmed as being localized to the injection site. In contrast, after injection into tau transgenic animals, aggregates develop not only at the injection site but spread to anatomically connected brain regions mirroring the highly predictable histopathological pattern of disease dissemination observed in AD patients (Clavaguera et al. 2009). Taken together, these findings indicate that tau aggregation in host animals can be induced by exogenously administered tau aggregates and that their spreading requires the process of aggregate induction and is not simply caused by passive diffusion from the injection site and endocytosis of aggregates. Similar to -synuclein, tau is present in the extracellular space, e.Zinc Pyrithione g., in the interstitial fluid of the brain, CSF and cell culture supernatant (Yamada et al. 2011). Tau does not contain a conventional secretion signal, although its release seems to be a physiological process that occurs in the absence of neurodegeneration, since tau has been detected in the interstitial fluid of wild-type mice brains and is abundantly present in the CSF of healthy persons, although CSF concentrations increase dramatically after neuronal damage (Tarawneh and Holtzman 2010; Yamada et al. 2011). Exosome-associated tau has recently been described in culture medium and CSF, indicating an active exocytosis process.Fenoprofen However, the intracellular sorting mechanisms for exosomal/microvesicular release are unclear, as is the percentage of extracellular tau that stems from this pathway (Saman et al.PMID:23415682 2011). As in the case of synuclein, no comparative data regarding the neurotoxicity and seeding capacity of free and EMV-associated tau have been obtained so far. Exosomes from M1C cells contain tau and are enriched in dimeric and trimeric tau species and in threonine 181 phosphorylated tau (Saman et al. 2011). This supports the hypothesis that exosomes might carry oligomeric species that serve as a template or seed to induce aggregation in recipient cells. Whether oligomerization occurs within the exosome, promoted by the high local protein concentration and pH, or whether oligomerized protein is specifically sorted to exosomes, as has been described for membrane-bound proteins (Shen et al. 2011b), is unclear. Tau protein has been detected by immuno-electron microscopy at the surface of EMVs derived from M1C cells and human CSF; however, these results have to be considered withcaution, since.