Investigating the mechanisms of synapse loss and tau propagation in progressive supranuclear palsy

Abstract

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 hypotheses that pathological tau and glia directly contribute to synapse loss and that tau pathology spreads between brain regions in PSP by moving from pre- to post-synapses. Subdiffraction-limit microscopy of human post-mortem PSP and control brain samples (n = 7) 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 taucontaining pre-synapse. In living human brain slice cultures (n = 5) PSP-derived oligomeric tau was taken up by post-synapses. Increased synaptic engulfment by astrocytes was observed in both post-mortem PSP brain and human brain slice cultures challenged with PSP-derived tau, whereas no increase in microglial synaptic engulfment was observed. Linear mixed-effect modelling was employed to analyse this data. An unbiased proteomics analysis of PSP total brain homogenate and biochemically isolated synapses (n = 10) supports the presence of neuroinflammation, astrocytic and synaptic changes in PSP brain, and highlights the need for further investigation into clusterin and syntaxin-6 as potential modulates of trans-synaptic tau propagation.

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, tau pathology propagation and disease progression in PSP.