Presenter of 1 Presentation
AMYLOID FACILITATED TAU-SEEDING AND SUBSEQUENT TAU-INDUCED NEURODEGENERATION: RECAPITULATING THE A/T/N-AXIS IN VIVO
Abstract
Aims
Brains of AD patients are characterized by the presence of amyloid pathology, Tau-pathology and neurodegeneration, referred to as A-, T- and N-pathology respectively. These stages develop in a characteristic spatio-temporal way in AD patients. Previous publications demonstrated amyloid facilitated tau seeding of endogenous tau, highlighting the relevance of amyloid facilitated tau pathology. We now focused on the development of a preclinical model that recapitulates all aspects of ATN pathology, downstream of amyloid pathology.
Methods
Hereto, we analyzed the effect of amyloid pathology on Tau-seeded pathology, its propagation and subsequent neurodegeneration in crosses of TauP301S and 5xFAD mice.
Results
Tau-seeded Tau-pathology was significantly increased in the presence of amyloid pathology. Tau-pathology propagated more efficiently to functionally connected brain areas at the ipsi- and contralateral side, remote from the injection site in the presence of amyloid pathology. Most strikingly, in the presence of amyloid pathology, Tau-seeding induced significant hippocampal and cortical atrophy, correlating with the level of Tau-pathology. Finally, microgliosis significantly increased at the different stages of the ATN axis in this model.
Conclusions
Our in vivo model displays amyloid facilitated propagation of Tau-seeded pathology and Tau-induced neurodegeneration. We here present a model robustly recapitulating the ATN pathologies, providing a tool to gain mechanistic insights in the interrelation and synergism between A, T and N pathologies to gain insight in the progressive development of ATN pathologies in AD.