Spreading of Tau Pathology in Mouse Models Expressing Pro-aggregant vs. Anti-aggregant Tau

Sara Rodrigues1, Marta Anglada1, Eckhard Mandelkow1, Eva-Maria Mandelkow1

1 DZNE, German Center for Neurodegenerative Diseases, Venusberg-Campus 1, Gebäude 99, 53127 Bonn, Germany; CAESAR, Center for Advanced European Studies and Research, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany

Objectives: We are studying the mechanisms underlying the onset and spreading of Tau pathology in the brain to obtain insights on the nature of the propagated Tau species and the role of the aggregation potential of Tau.

Methods: Mice are stereotactically injected in the entorhinal cortex (EC) with adeno-associated virus (AAV) encoding full length human Tau (2N4R) carrying either the deletion mutation ΔK280 (pro-aggregant), or the mutation ΔK280/I277P/I308P (anti-aggregant). Time points for molecular and histological analysis are 3, 6, 12 and 18 months post-injection.

Results: We observe a similar time-dependent spreading pattern of pro- and anti-aggregant tau protein from the EC to the hippocampus, along the perforant pathway. On the other hand, pathological markers, including Tau phosphorylation (antibodies AT8, PHF-1) and pathological conformation (antibody MC1) are more prominent in the pro-aggregant model, and restricted to the EC and the perforant pathway. Inflammatory markers are also increased in the pro-aggregant mice, and the appearance of inflammation precedes the trans-synaptic spreading of pro-aggregant Tau from the EC to the hippocampus.

Conclusions: The aggregation propensity of Tau protein does not affect the spreading from the EC to the DG along the perforant pathway, but determines the extent of pathology being developed (hyperphosphorylation and misfolding). Curiously, the increase in neuroinflammatory markers precedes the trans-synaptic spreading of human Tau from the EC to the DG, suggesting the existence of a signaling mechanism from the EC to the hippocampus that triggers the development of neuroinflammation, prior to the development of Tau pathology.