Tau accumulates in synaptogyrin-3 positive synapses in Progressive Supranuclear Palsy

In the neurodegenerative disease Progressive Supranuclear Palsy (PSP), tau pathology progresses through the brain in a stereotypical spatiotemporal pattern, and where tau pathology appears, synapses are lost. We tested the hypothesis that tau pathology spreads between brain regions in PSP by moving from pre- to post-synapses. Sub-diffraction-limit microscopy of human post-mortem brain samples revealed that oligomeric tau is present in synaptic pairs in PSP, with an 80-fold increased chance of post-synapses containing tau when they oppose a tau-containing pre-synapse. In living human brain slice cultures, PSP-derived oligomeric tau was taken up by post-synapses. Synaptic engulfment by astrocytes was observed in both post-mortem brain and human brain slice cultures challenged with PSP-derived tau. These data indicate that tau pathology spreads via synapses in PSP and that astrocytes contribute to synapse loss. Targeting synaptic tau and astrocyte-mediated phagocytosis of synapses are promising targets for attenuating synaptic loss and pathology propagation in PSP.