An AAV model of tauopathy targeting the mouse dentate gyrus reveals greater trans-synaptic tau spreading with aggregation-prone tau variants

Alzheimer's disease is characterized by progressive memory and cognitive decline, which is strongly correlated with the anatomical progression of tau pathology. Resulting from the intraneuronal aggregation of misfolded tau protein, tauopathy propagates in an anterograde manner between synaptically connected neurons through a prion-like mechanism. While glial cells, particularly microglia, are implicated in this process, the precise mechanisms underlying tauopathy propagation remain poorly understood. A critical unresolved question is whether aggregated or soluble pathologic tau forms mediate this spread. Here, we show in vivo that tau spreading scales with the aggregation propensity of the tau variant expressed. We developed a mouse model using adeno-associated virus (AAV)-mediated gene transfer to overexpress distinct tau forms in the dentate gyrus, alongside a reporter gene. This design enabled discrimination between transduced neurons and those secondarily affected by pathology propagation. Leveraging contralateral neuronal projections, we quantified propagation levels. To investigate the role of microglia and of extracellular vesicles, we analyzed microglial morphology in response to different tau forms and measured tau protein levels in extracellular vesicles isolated from injected mouse brains. We first confirmed the presence of vector-derived tau protein in non-transduced neurons, validating our model for studying tau propagation. We then found that aggregation-prone tau variants were associated with a greater number of tau-positive neurons in the contralateral hippocampus than wild-type tau. Additionally, extracellular vesicles from brains injected with aggregated tau contained higher levels of tau protein. Given that insoluble tau aggregates represent the ultimate stage of tauopathy, our findings suggest that propagation occurs at advanced stages of tau pathology, and that extracellular vesicles may contribute to the transfer of pathological tau, although the cellular origin of these vesicles was not determined in this study. Furthermore, our model provides a robust experimental paradigm for exploring therapeutic strategies aimed at inhibiting tauopathy propagation.