DEVELOPING IN VIVO MODELS OF TAU PROPAGATION WHICH ARE RELEVANT TO HUMAN DISEASE PATHOGENESIS AND APPLICABLE TO PRE-CLINICAL DRUG DISCOVERY

Abstract

Recent advances in our understanding of tau pathophysiology, in particular “prion-like” spread of tau, have only highlighted pathological tau as a prime therapeutic target for Alzheimer's disease (AD) and other tauopathies. Tau aggregates can act as ‘seeds’ that promote further tau aggregation and spread to structurally connected brain regions; a process termed tau propagation. Although the exact mechanism(s) involved are not fully understood, numerous in vivo models of tau propagation have been developed. These models rely on either discrete regional tau over-expression or intracerebral infusion of tau aggregates; however, are these models relevant to human disease and preclinical drug-discovery? In this study we compare and contrast a range of in vivo models we have developed and optimised for pre-clinical drug-discovery. Tau transgenic (P301S and hTau) and wild-type (C57/BL6) mice were stereotaxically infused with tau protein extracted from mouse brain (P301S and C57/BL6) or post-mortem AD brain tissue. Mice were analysed neuropathologically at defined time-points post-infusion to analyse the accumulation and spread of tau pathology. Tau extracts prepared from C57/BL6 mice did not induce tau propagation in vivo. In contrast, rapid and robust tau propagation was observed when P301S mice were infused with tau extracts derived from symptomatic P301S mice; however, such accumulation and spread of tau pathology was not observed when the same seed was infused into hTau mice. Interestingly, tau protein extracts derived from post-mortem AD brain tissue had variable results on the distribution, progression and severity of tau pathology when infused into different transgenic and wild-type mice. Immunodepletion of pathological tau from the extract prevented any tau accumulation or spread. We have developed and optimised a range of in vivo tau propagation models that demonstrate seeded-aggregation and spread of tau pathology. The severity, distribution and progression of tau pathology were different in these models and therefore will affect their utility and relevance for pre-clinical drug-discovery.