IDENTIFICATION OF NOVEL TARGETS FOR INHIBITING PRION-LIKE SEEDING AND PROPAGATION OF TAU PATHOLOGY IN VITRO AND IN VIVO

Abstract

In AD, Tau pathology progresses in a stereotypic spatiotemporal pattern, strongly correlating with progression of disease symptoms. Prion-like propagation of Tau-pathology, or propagation of Tau-misfolding between cells and functionally connected brain regions, provides a compelling mechanism for this stereotypic progression of Tau-pathology, and hence an attractive therapeutic target. To test and validate novel therapeutic targets capable of inhibiting prion-like progression of Tau-pathology, we have generated combined in vitro and in vivo models recapitulating prion-like seeding and propagation of Tau-pathology. Seeding of pre-aggregated Tau in Tau expressing primary neurons and Tau transgenic mice recapitultes strong induction of Tau-pathology and propagation to the contralateral side. Using these models we have analysed and evaluated the modifying potential of different targets on Tau pathology and propagation of Tau pathology. Targets under evaluation encompass Tau-interactome based Tau interacting proteins, including OTUB1 and other identified Tau-interacting proteins, as well as hypothesis based analysis. Within this analysis we identified OTUB1 as Tau deubiquitinase, involved in the accumulation of pathological forms of Tau. We furthermore identified novel targets with modifying effect on prion-like seeding and propagation of Tau-pathology. We here present the identification of different targets with a modulatory effect in vitro and in vivo on Tau-pathology and prion-like propagation of Tau-pathology.