Neural Circuits & Behavior Progress Report // Galina Limorenko - Development and validation of in vitro, in cellulo and in vivo models to elucidate the roles of Tau proteoforms in regulating Tau aggregation, seeding and pathology spreading

The microtubule-binding protein Tau is an intrinsically disordered protein, in cells most prominently associated with dynamic regulation and stabilisation of cytoskeletal and mitotic microtubules. Increasing evidence points to Tau aggregation and post-translational modifications, such as truncation, as central events in the pathogenesis of AD and Tauopathies. Truncated Tau fragments derived from AD patients’ brain and CSF have been shown to possess Tau nucleating and templated seeding competency in vitro, in cell culture and in vivo models of Tauopathies. Nevertheless, the molecular and cellular factors that trigger Tau misfolding and aggregation, as well as which Tau species initiate and/or drive Tau pathology and spreading in the brain remain unknown. In addition, no in vitro, cellular or animal models accurately recapitulate the Tau aggregation, seeding and spreading mechanisms.
To address these issues as a part of my project I aim to conduct a systematic investigation of the Tau truncation products’ role in regulating Tau aggregation, seeding and pathology spreading in vitro, in in cellulo model of Tau seeding and aggregation, and in vivo models of Tau pathology spreading. On the basis that shorter fragments of Tau exhibit high aggregation propensity we hypothesise that the aggregation of Tau fragments could play central roles in the initiation of the aggregation of the full-length Tau proteins and may even regulate the cell-to-cell propagation of Tau pathology.
During this seminar, I will present the overview of the Tau investigation field and methodology state of the art, and will present the recent achievements from our laboratory of in vitro Tau protein system that most closely recapitulates the Tau fibril structures found in human brain, providing an efficient in vitro platform for Tau aggregation studies. Further, I will outline the steps towards the development of the bona fide cellular model of Tau aggregation and in vivo model of Tau pathology spreading.
Development of efficient Tau proteoform aggregation assessment pipeline will help accelerate the identification of novel biomarkers and targets and pave the way for developing novel diagnostic and therapies for AD and non-AD tauopathies.