O5‐04‐01: MOLECULAR MECHANISMS OF ABETA‐INDUCED TAU‐PATHOLOGY: ANALYSIS OF CROSS‐SEEDING OF ABETA AND TAU AND ITS ROLE IN PRION‐LIKE PROPAGATION OF TAU‐PATHOLOGY IN VITRO AND IN VIVO

Combined genetic, pathological and clinical data provided the basis for the amyloid cascade hypothesis, which is further supported by biomarker data and remains the major hypothesis for development of therapeutic strategies. In vitro and preclinical in vivo models have robustly recapitulated amyloid induced Tau-pathology providing support to the amyloid cascade hypothesis and providing tools to understand this event, generally considered to be crucial in the pathogenesis of AD. We previously reported a preclinical model with robust amyloid induced Tau-pathology, providing an experimental window for analysis of mechanisms of ABeta-induced Tau-pathology in vivo. In this model, we demonstrated the induction of Tau-pathology along functional connections, in regions relatively spared of amyloid pathology. The striking similarity between abeta-induced Tau-pathology in preclinical models and in our recently reported Tau-seeding model, provided the basis for our current analysis of Abeta-induced Tau-fibrillization by cross-seeding and its subsequent propagating potential, in vitro and in vivo. Cell –free assays were used to analyze Tau fibrillization by different forms of ABeta using ThioT, sedimentation analysis and electron microscopy. Furthermore, a previously characterized cellular assay of Tau-aggregation and in vivo seeding models, have been used to analyze cross-seeding of Tau fibrillization by ABeta and its subsequent propagation potential. We demonstrate that different forms of pre-aggregated Abeta induce Tau-fibrillization in a cell-free assay, with varying efficiencies. In addition, we demonstrate that different forms of pre-aggregated ABeta induce Tau-aggregation in a cellular assay of Tau-seeding and Tau-aggregation with different efficiencies. The developed assays of cross-seeding are further used to analyze the molecular and cellular mechanisms of seeded Abeta-induced Tau-aggregation. Finally, we demonstrate that Abeta-seeded Tau provides potent seeds for induction and prion-like propagation of Tau-pathology in Tau transgenic mice in vivo. Different forms of pre-aggregated Abeta are demonstrated to cross-seed Tau fibrillization. Cross-seeding between ABeta and Tau provides a compelling mechanism for conversion of Tau-pathology from a silent to an aggressive propagating Tau strain associated with neuronal dysfunction. Cross-seeding of Tau-aggregation thereby presents as an attractive mechanism for Abeta-induced Tau-pathology observed in preclinical models and for the initiation of propagation of Tau-pathology observed in patients.