Super-resolution imaging unveils the self-replication of tau aggregates upon seeding

Dimou, Eleni; Katsinelos, Taxiarchis; Meisl, Georg; Tuck, Benjamin J.; Keeling, Sophie; Smith, Annabel E; Hidari, Eric; Lam, Jeff; Burke, M.G.; Lövestam, Sofia; Ranasinghe, Rohan T.; McEwan, William A.; Klenerman, David

doi:10.1016/j.celrep.2023.112725

Cited by 15 publications

(4 citation statements)

References 74 publications

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“…A few aggregates were spherical, but most were irregular in appearance. A few had a linear appearance that resembled the seeded aggregates previously observed in proximity to microtubules (54). Individual cells were tracked, allowing for the quantification of the total area occupied by aggregates, the average size of aggregates, and the number of aggregates per cell.…”

Section: Dynamics and Heterogeneity Of Tau Aggregatesmentioning

confidence: 90%

Precision Proteoform Design for 4R Tau Isoform Selective Templated Aggregation

Longhini,

DuBose,

Lobo

et al. 2023

Preprint

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Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. We used a 19-residue probe peptide spanning the R2/R3 splice junction of tau to induce aggregation specifically of 4R, but not 3R tau. The aggregates can propagate as isoform-specific seeds over multiple generations, have a high β-sheet content, a lipid signal, and resemble the PSP cryo-EM fold. A simulation of peptide free energy landscapes pinpointed the features of the hairpin structure uniquely found in the cryo-EM structures of pure 4R tauopathies and captured in the peptide. These molecular dynamic simulations were experimentally validated by the S305K substitution in 4R tau, corresponding to the position found in 3R tau. This single amino acid substitution prevented tau aggregates induced by the prion-like probe peptide. The tau aggregates were dynamic and displayed growth, stability, and shrinking over time. These results could serve as the basis for tau isoform-specific therapeutic interventions.

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Section: Dynamics and Heterogeneity Of Tau Aggregatesmentioning

confidence: 90%

Precision Proteoform Design for 4R Tau Isoform Selective Templated Aggregation

Longhini,

DuBose,

Lobo

et al. 2023

Preprint

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“…Several cellular models of tau aggregation induced by seeded tau exposure have been developed 67 68 69 70 71 72 . However, the cellular mechanism and tau aggregation pathway that convert normal tau to seed-active tau remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Tau Fragment Droplets Serve as Seeds for Tau Fibrils

Soeda,

Yoshimura,

Bannai

et al. 2023

Preprint

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Intracellular tau aggregation requires a local protein concentration increase, referred to as droplets. However, the cellular mechanism remains insufficiently understood. We expressed OptoTau, a fusion of P301L mutant tau with CRY2olig, a light-sensitive protein that forms homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment, which can dissolve droplets, suggesting that intracellular tau droplet formation requires the microtubules collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau that was observed in the Alzheimer’s disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm by blue light stimulation. This intracellular stable tau clusters acted as seeds for tau fibrils in vitro. These results suggest that both tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.

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“…To characterize aggregate morphology with a precision unattainable via diffraction-limited imaging, we adapted MAPTau for super-resolution microscopy, specifically Stochastic Optical Reconstruction Microscopy (STORM), [30] which has previously been used to image intracellular tau aggregates. [31,32] Combining MAPTau with STORM, we were able to quantify the length, perimeter, total area, and eccentricity of individual tau aggregates in brain homogenate. We observed two dominant aggregate shapes, loosely falling into extended 'fibrillar' and short 'globular' categories (Figure 3A and B and Supplementary Figure S2A).…”

Section: Super-resolved Maptau Quantifies Aggregate Morphology With S...mentioning

confidence: 99%

Single‐Molecule Characterization and Super‐Resolution Imaging of Alzheimer's Disease‐Relevant Tau Aggregates in Human Samples

Böken,

Cox,

Burke

et al. 2024

Angewandte Chemie

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Hyperphosphorylation and aggregation of the protein tau play key roles in the development of Alzheimer’s disease (AD). While the molecular structure of the filamentous tau aggregates has been determined to atomic resolution, there is far less information available about the smaller, soluble aggregates, which are believed to be more toxic. Traditional techniques are limited to bulk measures and struggle to identify individual aggregates in complex biological samples. To address this, we developed a novel single‐molecule pull‐down‐based assay (MAPTau) to detect and characterize individual tau aggregates in AD and control post‐mortem brain and biofluids. Using MAPTau, we report the quantity, as well as the size and circularity of tau aggregates measured using super‐resolution microscopy, revealing AD‐specific differences in tau aggregate morphology. By adapting MAPTau to detect multiple phosphorylation markers in individual aggregates using two‐color coincidence detection, we derived compositional profiles of the individual aggregates. We find an AD specific phosphorylation profile of tau aggregates with more than 80% containing multiple phosphorylations, compared to 5% in age‐matched non‐AD controls. Our results show that MAPTau is able to identify disease‐specific subpopulations of tau aggregates phosphorylated at different sites, that are invisible to other methods and enable the study of disease mechanisms and diagnosis.

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Super-resolution imaging unveils the self-replication of tau aggregates upon seeding

Cited by 15 publications

References 74 publications

Precision Proteoform Design for 4R Tau Isoform Selective Templated Aggregation

Precision Proteoform Design for 4R Tau Isoform Selective Templated Aggregation

Intracellular Tau Fragment Droplets Serve as Seeds for Tau Fibrils

Single‐Molecule Characterization and Super‐Resolution Imaging of Alzheimer's Disease‐Relevant Tau Aggregates in Human Samples

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