In situ cryo-EM of tau filaments in brain extracellular vesicles in Alzheimer’s disease

The assembly of tau protein in the brain underlies many neurodegenerative diseases, including Alzheimer's disease (AD). Evidence suggests that extracellular vesicles (EVs) facilitate assembled tau clearance and transfer between neurons. However, the molecular mechanisms are unknown. Here, using cryo-electron tomography and subtomogram averaging, Behr and colleagues directly visualised tau paired helical filaments (PHFs) and straight filaments (SFs) within the lumen of EVs from AD patient brain. This revealed that PHFs and SFs associate with one another and are tethered to the EV limiting membrane at their ends. Single particle cryo-electron microscopy revealed that the PHFs contain additional negatively-charged molecules compared to PHFs within neuronal inclusions, resulting in a more compact filament fold. Their findings will inform strategies to target the clearance and spread of assembled tau in AD and other neurodegenerative diseases. This work paves the way for further in situ structural studies of neurodegenerative disease-associated filaments in near-native conditions in human brain.