Researchers Develop Breakthrough Technique for Mapping Alzheimer’s Proteins

A team of researchers from Israel and the Netherlands has introduced a groundbreaking technique that enables precise measurement of toxic protein clumps associated with Alzheimer’s disease. This innovation could significantly enhance the study and diagnosis of dementia. The technology, known as FibrilPaint in conjunction with the FibrilRuler test, allows scientists to measure the length of Tau amyloid fibrils in fluid, even at extremely low concentrations.

The study was led by Prof. Assaf Friedler from the Institute of Chemistry at Hebrew University of Jerusalem and Prof. Stefan GD Rudiger from Utrecht University. Their findings were published on December 14, 2023, in the peer-reviewed journal Proceedings of the National Academy of Sciences. The accumulation of Tau proteins in the brain is a hallmark of Alzheimer’s and several other neurodegenerative disorders.

Tau proteins are critical for maintaining the structure and function of nerve cells. However, when these proteins misfold, they form elongated amyloid fibrils that correlate with disease progression. Despite their importance, measuring the length of these fibrils directly in solution has posed significant challenges for scientists.

“The length of Tau fibrils is not just a detail — it is a key parameter of the disease process,” stated Friedler. Traditional methods often rely on microscopy or biochemical techniques that require large quantities of material or remove fibrils from their natural environment, providing only indirect estimates of size. These limitations hinder researchers’ ability to observe how fibrils grow or respond to potential treatments.

The innovative approach features FibrilPaint1, a 22-amino acid peptide engineered to serve as a selective fluorescent probe. Unlike conventional dyes, this probe binds specifically to amyloid fibrils, allowing researchers to differentiate harmful structures from benign proteins. “We wanted a probe that behaves like a smart key,” Rudiger explained. “It finds amyloid fibrils, including very early ones, and ignores the rest of the crowded biological environment.”

FibrilPaint1 has the ability to recognize a wide range of Tau fibrils derived from various diseases, including Alzheimer’s disease, corticobasal degeneration, and frontotemporal dementia. It also binds to fibrils formed by other disease-related proteins, such as Amyloid-beta and alpha-synuclein, while maintaining low background binding to non-amyloid aggregates.

To transform FibrilPaint1 into a quantitative measuring tool, the researchers integrated it with a microfluidics technique called flow-induced dispersion analysis. During the FibrilRuler test, FibrilPaint1 binds to fibrils in solution, and the sample is then passed through a microscopic capillary. The behavior of the fluorescent signal during this process reveals the effective size of the fibril-probe complex, enabling direct calculations of fibril length.

“This is essentially a molecular ruler that works inside the fluid itself,” Friedler noted. The research team achieved measurements of Tau fibrils ranging from as few as four molecular layers to over 1,100 layers, even at nanomolar concentrations. Such levels of sensitivity and resolution had not been previously attainable for amyloid fibrils in solution.

The implications of this technique extend beyond academic research into Alzheimer’s disease. By allowing scientists to measure Tau fibril lengths directly in complex biological mixtures, it becomes possible to monitor how these toxic structures form, grow, and break apart over time. Researchers can now investigate the earliest stages of fibril development, compare samples from different diseases, and assess how environmental factors influence fibril behavior.

In the long run, this approach may also expedite drug development and inform future diagnostic methods. “If we can directly measure amyloid fibril size in patient material, such as cerebrospinal fluid, we may gain a new type of biomarker for dementia,” Rudiger added. While the researchers acknowledge that further development and validation are necessary for clinical application, the potential of this new technique represents a significant advancement in the ongoing battle against Alzheimer’s disease.