Spreading of Tau Protein Does Not Depend on Aggregation Propensity

The stereotypical progression of Tau pathology during Alzheimer disease has been attributed to trans-neuronal spreading of misfolded Tau proteins, followed by prion- like templated aggregation of Tau. The nature of Tau and the cellular mechanisms of Tau spreading are still under debate. We hypothesized that Tau's propensity for aggregation would correlate with its ability to spread across synapses and propagate pathology. To study the progressive propagation of Tau proteins in brain regions relevant for Alzheimer disease, we used mice expressing near- physiological levels of full-length human Tau protein carrying pro-aggregant (Tau Delta K280, Tau(Delta K)) or anti-aggregant (Tau Delta K280-PP, Tau(Delta K- PP)) mutations in the entorhinal cortex (EC). To enhance Tau expression in the EC, we performed EC injections of adeno-associated virus (AAV) particles encoding Tau(Delta K) or Tau.(Delta K- PP). The brains of injected and non-injected EC/Tau(Delta K) and EC/Tau(Delta K-PP) mice were studied by immunohistological and biochemical techniques to detect Tau propagation to dentate gyrus (DG) neurons and Tau-induced pathological changes. Pro- and anti-aggregant mice had comparable low transgene expression (similar to 0.2 times endogenous mouse Tau). They accumulated human Tau at similar rates and only in expressing EC neurons, including their axonal projections of the perforant path and presynaptic terminals in the molecular layer of the DG. Pro-aggregant EC/Tau.K mice showed misfolded Tau and synaptic protein alterations in EC neurons, not observed in anti-aggregant EC/Tau.K-PP mice. Additional AAV-mediated expression of Tau(Delta K) or Tau(Delta K- PP) in EC/Tau.K or EC/Tau.K-PP mice, respectively, increased the human Tau expression to similar to 0.65 times endogenous mouse Tau, with comparable spreading of Tau.K and Tau(Delta K- PP) throughout the EC. There was a low level of transcellular propagation of Tau protein, without pathological phosphorylation or misfolding, as judged by diagnostic antibodies. Additionally, Tau.K but not Tau.(Delta K -PP) expression induced hippocampal astrogliosis. Low levels of pro- or anti-aggregant full-length Tau show equivalent distributions in EC neurons, independent of their aggregation propensity. Increasing the expression via AAV induce local Tau misfolding in the EC neurons, synaptotoxicity, and astrogliosis and lead to a low level of detectable trans-neuronal spreading of Tau. This depends on its concentration in the EC, but, contrary to expectations, does not depend on Tau's aggregation propensity/misfolding and does not lead to templated misfolding in recipient neurons.

Automated summary

The progression of Tau pathology in Alzheimer's disease is believed to be due to the spread of misfolded Tau proteins and their aggregation. This study investigates the correlation between Tau's aggregation propensity and its ability to spread across synapses. The findings suggest that the concentration of Tau in specific brain regions plays a role in its propagation, independent of its aggregation propensity. Additionally, the study highlights the role of Tau in synaptic toxicity and astrogliosis.