TAU PATHOLOGY PROPAGATES THROUGH NEURAL NETWORKS IN TAU22 MICE AFTER INJECTION OF SYNTHETIC TRUNCATED TAU AGGREGATES IN DORSAL HIPPOCAMPUS

Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of tau protein aggregates, for which there is a large unmet medical need for disease-modifying therapies. The concept of transmission and propagation of tau pathology has emerged in the clinic and has been reinforced by studies in cellular and animal models showing that exogenous tau aggregates may trigger the misfolding and aggregation of endogenous tau (seeding) and propagate to interconnected neurons (spreading). Here we characterized such an in vivomodel of tau propagation in TAU22 mice with cognitive, biochemical and histological markers. Two month old transgenic Tau22 heterozygous male mice (Thy1.2-promotor, 2N4R tau, G272V/P301S) were injected unilaterally in the dorsal hippocampus with mutated-microtubule binding repeat (mut-MTBR) domain tau aggregates (6.75μg/2.5μl) or vehicle. Tau pathology was evaluated 2, 4, 9 and 12 weeks after injection by quantification of AT8 and Gallyas staining in several brain regions by immunohistochemistry. The impact on cognition was evaluated 4 weeks after injection using the object recognition task and tissue tau aggregates were measured in several brain structures using HTRF®technology. Injection of mut-MTBR aggregates in the dorsal hippocampus induced a progressive accumulation of Gallyas and AT8 positive cells in the ipsi- and contralateral CA3/ hippocampus, the ipsilateral entorhinal cortex and the ipsi- and contralateral lateral septum. Four weeks after injection, mice exhibited a significant cognitive deficit compared to vehicle-injected Tau22 mice. In addition, we observed an increase in tissue tau aggregates which correlated with the accumulation of AT8 and Gallyas positive cells. We have developed an in vivo mouse model of seeding of endogenous Tau and propagation of Tau pathology. The anatomical distribution of tau pathology in this model could be due either to tau spreading or to retrograde transport of tau seeds. Additional studies exploring different injection sites of pathologic Tau will be needed to develop an in vivo model of trans-synaptic spread.