Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation

• Synaptic and non-synaptic mechanisms each contribute to tau pathology spreading
• Synaptic contacts, but not mere close proximity, enhance tau pathology spreading
• Quantitative in vitro cellular synaptic systems allow modeling of tau spreading
• Synaptic cell adhesion proteins and neuronal activity promote tau spreading

SummaryAccumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer’s disease (AD). Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation. These findings can have implications for synaptic repair therapies, which may turn out to have adverse effects by promoting propagation of Tau pathology.

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