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CRYO-ELECTRON MICROSCOPY OF EXTRACELLULAR VESICLES CONTAINING AGGREGATED TAU IN ALZHEIMER'S DISEASE
Abstract
Aims
In Alzheimer’s disease tau aggregation begins in subcortical regions and spreads sequentially to the transentorhinal cortex, limbic system and neocortex along neuronal connections. It has been shown that extracellular vesicles, a heterogeneous group of secreted vesicles, can mediate cell to cell spreading of aggregated tau. However, the molecular identities of the aggregated tau species and extracellular vesicles are not known.
Methods
We used cryo-electron microscopy to visualise aggregated tau associated with extracellular vesicles from the brains of individuals with Alzheimer's disease. Cryo-electron tomography was used to reveal the molecular composition of intact extracellular vesicles and single particle cryo-electron microscopy was used to determine the structures of aggregated tau associated with extracellular vesicles.
Results
We found paired helical and straight tau filaments densely packed within double-membraned vesicles of between 300 and 750 nm in diameter. We found evidence for tethering of filaments to the inner vesicle membrane via adaptor proteins, with additional filaments tethered to one another and to internal vesicles in a network. Tau filaments were decorated with additional globular protein densities at ordered positions along the long filament axis. We determined the structure of the ordered core of tau filaments following detergent extraction from extracellular vesicles. This revealed the presence of negatively-charged molecules associated with the side chains of R349 and K375 that were not observed in filaments extracted from total brain homogenates.
Conclusions
Our results give molecular insights into extracellular vesicles containing aggregated tau in Alzheimer's disease, which will inform strategies to target the spread of aggregated tau.