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- W2065629420 abstract "Our group has shown in two models with tangle pathology that immunization with an AD specific phospho-tau epitope slows the progression of tangle-associated phenotype, reduces tau aggregates and prevents cognitive impairments (Asuni A. et al. J. Neurosci., 2007, Sigurdsson E.M. et al., ICAD Chicago, 2008). Additionally, we demonstrated that immunization against a phospho-tau epitope located within the microtubule binding region could also clear tau aggregates and reduce functional deficits in a mouse model of tauopathy (Krishnamurthy P.K. et al., ICAD Vienna, 2009). A natural follow up of these studies is to understand the cellular mechanisms involved in this phenomenon. Therefore, the uptake and localization of FITC labeled anti-tau antibodies was studied in an organotypic brain slice model derived from adult JNPL3 (P301L) mice with established tau pathology. Brain slices were prepared, allowed to stabilize and incubated with FITC-IgG for two hours at 35 °C with intermittent oxygenation. The IgG was purified from an immunized P301L mouse with a high antibody titre against our phos-tau immunogen (Tau 379-408[pSer396,404]). Slices (400 μm) were fixed in PLP and 40 μm sections from their center were stained with the tau antibodies CP13 (pSer202 epitope) and MC1 (conformational epitope) and a Texas Red conjugated secondary. Sections were also stained with antibodies against LAMP2 and rab5, markers of lysosomes and early endosomes respectively. All sections were counterstained with the nuclear marker Hoescht 33342 and visualized by confocal microscopy. Extensive but partial co-localization was observed between FITC-IgG and the tau antibodies CP13 and MC1. Furthermore, we determined that the FITC-IgG was completely associated with cellular markers of lysosomes, LAMP2, and early endosomes, rab5, with perinuclear vesicles as the main areas of co-staining. In wild-type mice, limited non-specific FITC-IgG binding was observed. Biochemical studies are underway to examine antibody compartmentalization. We are assessing as well the ubiquitin-proteosome system that is probably not involved as it is likely saturated under these conditions. These findings indicate that the endosomal-lysosomal pathway is involved in antibody-mediated clearance of tau aggregates. Patent pending on tau immunotherapy." @default.
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- W2065629420 date "2010-07-01" @default.
- W2065629420 modified "2023-09-27" @default.
- W2065629420 title "P1-355: Mechanistic studies of antibody mediated clearance of tau aggregates using an ex vivo brain slice model" @default.
- W2065629420 doi "https://doi.org/10.1016/j.jalz.2010.05.909" @default.
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