Real-time imaging and mechanistic analysis of Tau fibril disaggregation in live cells

Informations projet

Tau DG RT-imaging

N° de convention de subvention: 101061411

DOI

10.3030/101061411

Projet clôturé

Date de signature de la CE 20 Juin 2022

Date de début 1 Septembre 2023

Date de fin 31 Août 2025

Financé au titre de

• Marie Skłodowska-Curie Actions (MSCA)

Coût total

Aucune donnée

Contribution de l’UE

€ 173 847,36

Coordonné par

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 1 - Tau DG RT-imaging (Real-time imaging and mechanistic analysis of Tau fibril disaggregation in live cells)

Période du rapport: 2023-09-01 au 2025-08-31

Résumé du contexte et des objectifs généraux du projet

Alzheimer’s disease and related brain disorders are among the most important medical challenges of our time. As people live longer, the number of patients continues to increase, placing enormous pressure on families, healthcare systems, and society. Current treatments provide only limited benefits, and new approaches are urgently needed.
One of the hallmarks of Alzheimer’s disease is the abnormal deposition of the protein Tau. Normally, Tau acts like the trees of a healthy forest, giving stability and structure to nerve cells. But under disease conditions, Tau changes its structure and becomes unstable. Like dry tinder ready to catch fire, misfolded Tau molecules act as sparks that ignite nearby healthy “trees” and ignite new fires. These sparks represent toxic protein clumps (so-called aggregates) that trigger a chain reaction, leading to the larger ‘fires’ of aggregation spreading from cell to cell. The build-up and multiplication of these toxic aggregates over time is thought to be one of the main drivers of dementia.
Past therapies mainly focused on removing the large “fires” or plaques in the brain. The results were modest and sometimes harmful, showing that tackling only the big flames is not enough. This project set out to understand how the first sparks appear in the form of small aggregates termed oligomers, how they spread through the forest, and how the brain’s natural “firefighters”, so-called molecular chaperones, try to put them out. By using advanced microscopy in living cells, we aimed to create a new framework for understanding Alzheimer’s disease and to pave the way for safer and more effective therapies.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

During the project, we developed cell models that allowed us to watch Tau proteins in action. With powerful microscopes, we could directly observe how Tau oligomers formed, how they developed into large aggregates, and how they sometimes dissolved.
Key achievements include:
Direct observation of Tau aggregate propagation: We demonstrated that pre-existing Tau aggregates can recruit soluble Tau molecules to form new aggregates, providing real-time evidence of how aggregation accelerates within cells.
Discovery of cellular triggers for aggregate nucleation: We identified an endogenous molecular chaperone factor that promotes the formation of oligomeric Tau species, indicating that nucleation does not occur spontaneously. Inhibiting this factor with specific compounds led to a marked reduction in toxic intermediates.
Clarification of the disaggregation mechanism: We found that VCP, together with Hsp70 and the proteasome, mediates Tau disaggregation through a sequential process. Inhibition at different stages produced distinct outcomes, showing that disaggregation is not a simple linear degradation pathway but a regulated, multi-step mechanism.
Development of a live-cell drug screening platform: We established an imaging-based system that allows early-stage evaluation of therapeutic compounds targeting toxic Tau oligomers, providing a more precise and efficient approach than conventional plaque-centered assays.
The project also provided training opportunities, fostered international collaboration, and supported younger researchers, building valuable skills for future careers.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

This project moved the field forward in several important ways:
Provided the first real-time evidence of how small Tau oligomers form and spread within living cells.
Elucidated how cellular proteostasis and chaperone systems act to suppress Tau aggregation and propagation, offering mechanistic insights relevant to therapeutic intervention.
Demonstrated why current therapies focusing solely on the removal of large aggregates may fail, as they overlook the smaller, highly toxic oligomeric species that drive disease progression.
Established experimental and analytical approaches that can be extended to other protein-misfolding disorders, including Parkinson’s disease, where similar aggregation mechanisms are involved.
Opened the way for future applications. We plan to test our findings further, validate them in other models, and seek patent protection for our live-cell screening system so that it can help design safer drugs targeting toxic species.

Tau sparks ignite cellular wildfires, while molecular firefighters fight to restore balance.