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ClearTau is a revolutionary approach and platform created by EPFL scientists for rebuilding clumps of the protein Tau seen in Alzheimer’s disease and other neurodegenerative Disease. The discovery could hasten the development of diagnostics and tailored treatments for Tau-related illnesses.
Tau is a protein discovered in the human brain that plays a vital role in nerve cell formation and function. When tau protein takes on atypical shapes, it can create clumps and tangles known as tau fibrils, which impede nerve cell communication. Tau fibrillation has long been linked to the progression of neurodegenerative disease such as Alzheimer’s and other “tauopathies.”
Understanding how Tau fibrils form and spread throughout the brain is critical in designing treatments to halt or reduce the progression of these disorders. However, research have been impeded since causing Tau misfolding and aggregation needs the inclusion of co-factors such as heparin.
Meanwhile, the generated tau fibrils differ significantly in structure and shape from those found in patient brain tissues. This has made developing medications and imaging technologies that track the production and spread of Tau aggregates in the brain or counteract their disease-causing qualities difficult.
ClearTau is a new, rapid, affordable, and effective process for manufacturing Tau fibrils without the need of co-factors invented by EPFL scientists. ClearTau enables the reconstruction of the complexity of aggregation present in the brains of tauopathies patients, as well as the development of disease-specific therapies and imaging tools.
ClearTau was co-invented by Galina Limorenko, a Ph.D. student at EPFL’s School of Life Sciences, and her supervisor, Professor HIlal Lashuel, and published in Nature Communications. ClearTau produces huge amounts of clean Tau fibrils faster than prior methods by using heparin that has been previously attached (“immobilized”) onto the surfaces of the tubes used to make Tau fibrils.
“The idea of clear Tau was inspired by technology often employed in the medical devices, such as blood perfusion or dialysis equipment, where immobilization of heparin molecules on the inner tubing is used to prevent blood clots while preventing its leakage into the bloodstream,” says Limorenko. “I thought, why not apply this to Tau?”
Limorenko and Lashuel thought that they could use immobilized heparin or other co-factors known to induce Tau aggregation to nudge the protein to change its shape and aggregate. “Because these co-factors are attached to the surface of the tube, they will not get stuck inside the growing Tau fibrils, change their structure or alter their normal interactions with other molecules,” says Limorenko. “We tried it and it worked.”
The researchers discovered that ClearTau can efficiently create all six Tau isoforms, as well as shortened and mutant variants, even in the presence of co-factor molecules other than heparin, such as RNA and ATP.
ClearTau eliminates the shortcomings of previous approaches, which either needed a significant amount of time or used uncharacterized co-factor components.
ClearTau fibrils are morphologically consistent within single Tau isoforms and exhibit key properties that distinguish them from their natural counterparts, such as amyloid reporter dye positivity, a high proclivity for binding RNA, and seeding competency—the ability of ClearTau aggregates to induce the aggregation of other Tau proteins in neurons, a “domino effect” that causes tauopathies.
We believe this work represents a major advancement if the field of Alzheimer’s disease and neurodegenerative disease research in general,” says Lashuel.
“Tau fibrils and aggregates in the brain are decorated with different types of chemical modifications, and interact with other non-proteinaceous molecules, whose identity remains unknown. Therefore, there is an urgent need for methods that allow for reconstructing the biochemical and structural complexity of the disease-associated Tau pathological aggregates.”
Lashuel adds, “By combining the ClearTau method with other technologies that our lab has pioneered over the years, and being able to decorate Tau molecules with chemical modifications similar to those found in disease, we now have a powerful platform that enables us for the first time to screen for and identify conditions that produce Tau aggregates that are chemically and structurally similar to pathological brain-derived forms.”
“This can help us develop disease-relevant models, design and validate novel therapies, identify new imaging agents for early diagnosis, monitor disease progression, and assess the efficacy of new therapies.”
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