Tau filaments found tethered inside Alzheimer’s brain exosomes

From Alzforum

Tau tangles accumulate within neurons, but they are also thought to travel from cell to cell via extracellular vesicles. A study posted April 30 on bioRXiv provides startling support for this idea. For the first time, scientists used cryo-electron tomography to spy on the spatial organization of proteins within vesicles isolated from the brains of people with Alzheimer’s disease. Why, hello there: They spotted filaments of tau nestled inside.

The filaments did not appear to have been sloppily shoved into these vesicles. Rather, an unidentified protein neatly tethered them to the vesicle inner membrane. Under the gaze of the cryo-electron microscope, the core of the filaments revealed a back-to-back C-shaped fold, akin to its counterpart extracted from AD brain lysates, albeit with some differences. Vesicle filaments were shorter, and decorated by unknown molecules that the scientists speculate may have ushered the tau inside.

Cryo-ET of extracellular vesicles containing tau PHFs and SFs
from Alzheimer’s Disease patient brain

(A) Denoised tomographic volume and segmentation of an EV from AD patient brain depicting the limiting membrane (yellow), intraluminal vesicles (cyan) and tau filaments (magenta).  (B) Denoised tomographic volumes of EVs from AD patient brain containing varying numbers of tau filaments. (C) Representative immunoblot of AD patient brain EVs from fractions 4–6 using antibody TauC with (+) or without (-) 0.1% Triton X-100 and 0.5 ng/µL proteinase K (PK). n=3. (D) Denoised tomographic slices of EVs from AD patient brain containing tau filaments. The arrows point to the minimum (filled arrows) and maximum (unfilled arrows) widths of tau PHFs (magenta arrows) and SFs (blue arrows). (E and F) Subtomogram averaged maps of tau PHFs (magenta) and SFs (blue) in EVs, shown as (E) central slices perpendicular to the helical filament axis and (F) 3D volumes encompassing one helical crossover. Scale bars, 200 nm in (A, B and D) and 10 nm in (E and F).

Led by Karen Duff at University College London and Benjamin Ryskeldi-Falcon of the Medical Research Council Laboratory of Molecular Biology, Cambridge, U.K., the scientists also reported that these tau filaments seeded propagation of tau pathology within cell lines and in transgenic mouse brain. In all, the study casts extracellular vesicles (EVs) as “good contenders” for tau transport vehicles, and illuminates “a whole new biology for tau,” Duff told Alzforum.

“The work by Fowler and colleagues is beautiful, and the images visualizing tau filaments within extracellular vesicles by cryo-electron microscopy are simply stunning,” commented Jürgen Götz at the University of Queensland, Brisbane, Australia.

Lary Walker of Emory University, Atlanta, noted that while the intercellular transfer of EVs within the brain can support homeostasis, it can also disseminate pathogenic protein seeds that drive neurodegenerative disease.

“The once-murky details of this remarkable mechanism are now yielding to increasingly sophisticated analyses, and the characterization of polymeric tau in Alzheimer brain-derived vesicles … is a welcome contribution,” he wrote to Alzforum (comments below).

From free-floating tau to tunneling nanotubes to EVs, different modes of transport have been proposed to explain the spread of tau pathology in tauopathies. EVs are an attractive option, because they could explain how tau appears to travel via synaptic circuitry and other routes.

Fowler SL, Behr TS, Turkes E, Cauhy PM, Foiani MS, Schaler A, Crowley G, Bez S, Ficulle E, Tsefou E, O’Brien DP, Fischer R, Geary B, Gaur P, Miller C, D’Acunzo P, Levy E, Duff KE, Ryskeldi-Falcon B. (2023) Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease. bioRXiv [online preprint]. [article]

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