Short tau filaments are packaged into extracellular vesicles in Alzheimer's disease brain

ABSTRACT: The abnormal higher-order assembly of tau protein in neurons and glia underlies a large group of neurodegenerative diseases, including Alzheimer's disease (AD). Tau assemblies are first detected in localised brain regions and subsequently accumulate in connected networks. Prion-like propagation is thought to underlie the temporospatial accumulation of assembled tau, encompassing intracellular trafficking and trans-synaptic transfer of assembled tau species that seed the assembly of normally folded tau. Evidence suggests that extracellular vesicles (EVs), a diverse group of lipid vesicles that facilitate the intercellular transfer of bioactive molecules, mediate transfer of assembled tau seeds. However, the molecular species of assembled tau seeds in human brain are unknown. Furthermore, the identities of the EVs that mediate intercellular transfer of assembled tau and how this is achieved have not been determined. Here, we isolated sub-populations of EVs from human brain enriched in plasma membrane; endo-lysosomal; or mitochondrial proteins. We used electron cryo-tomography (cryo-ET) and single-particle electron cryo-microscopy (cryo-EM) to directly analyse the structure and molecular organisation of assembled tau seeds associated with intact EVs isolated from the brains of individuals who had AD. We found that short tau paired helical filaments (PHFs) were packaged within the lumen of large EVs enriched in endo-lysosomal proteins. The PHFs incorporated anionic molecules not observed in cell-derived PHFs, leading to a more compact filament fold. Multiple PHFs associated with one another and were linked to the luminal membrane at their ends. The PHF-containing EVs initiated propagation in directly-converted neurons, as well as in transgenic mice and a biosensor cell line. This work suggests that short PHFs are responsible for EV-mediated propagation of assembled tau in human brain. These results have broad implications for diagnostic and therapeutic strategies targeting extracellular assembled tau seeds in AD and other neurodegenerative diseases.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Darragh O'Brien  

LAB HEAD: Roman Fischer

PROVIDER: PXD037708 | Pride | 2025-05-06

REPOSITORIES: Pride