Jerusalem, 14 December, 2025 (TPS-IL) — Israeli and Dutch researchers have unveiled a new technique that allows scientists to precisely measure toxic protein clumps associated with Alzheimer’s disease — something that has long been out of reach and could open new paths for studying and eventually diagnosing dementia.
The technology, known as FibrilPaint combined with the FibrilRuler test, makes it possible to directly measure the length of Tau amyloid fibrils while they are still suspended in fluid, even at extremely low concentrations. Because the buildup and growth of these fibrils are closely linked to Alzheimer’s disease and related dementias, the ability to quantify their size represents a major advance for the field.
The research was led by Prof. Assaf Friedler of the Institute of Chemistry at Hebrew University of Jerusalem and Prof. Stefan G. D. Rüdiger of Utrecht University, and was published in the peer-reviewed Proceedings of the National Academy of Sciences.
Alzheimer’s disease and several other neurodegenerative disorders are marked by the abnormal accumulation of Tau proteins in the brain. Tau proteins are normal, essential proteins in the brain that help nerve cells maintain their internal structure and function. But problems arise when Tau changes shape and begins to clump abnormally. Over time, these proteins misfold and assemble into elongated amyloid fibrils, structures believed to track with disease progression. Despite their importance, scientists have struggled to measure fibril length directly in solution under realistic biological conditions.
“The length of Tau fibrils is not just a detail — it is a key parameter of the disease process,” Friedler said. “Until now, it has been extremely difficult to measure fibril size directly in solution, especially at the tiny concentrations found in real biological samples.”
Most existing techniques rely on microscopy or bulk biochemical methods that require large amounts of material, remove fibrils from their natural environment, or provide only indirect estimates of size. These limitations have made it difficult to observe how fibrils grow, fragment, or respond to potential drugs and biological pathways.
At the heart of the new approach is FibrilPaint1, a short, 22–amino acid peptide engineered to act as a highly selective fluorescent probe. Unlike conventional dyes, FibrilPaint1 binds tightly to amyloid fibrils while ignoring individual Tau molecules that have not yet aggregated, allowing researchers to distinguish harmful structures from harmless proteins in complex samples.
“We wanted a probe that behaves like a smart key,” Rüdiger said. “It finds amyloid fibrils, including very early ones, and ignores the rest of the crowded biological environment. FibrilPaint1 does exactly that.”
The probe recognizes a broad range of Tau fibrils, including those derived from patients with Alzheimer’s disease, corticobasal degeneration, and frontotemporal dementia. It also binds fibrils formed by other disease-related amyloid proteins, such as Amyloid-β, α-synuclein, and huntingtin, while showing negligible background binding to blood serum, cell lysate, or non-amyloid aggregates.
To transform this selective probe into a quantitative measuring tool, the researchers combined it with a microfluidics technique known as flow-induced dispersion analysis. In the FibrilRuler test, FibrilPaint1 binds to fibrils in solution, and the sample flows through a microscopic capillary. The way the fluorescent signal spreads during flow reveals the effective size of the fibril–probe complex, allowing researchers to calculate fibril length directly.
“This is essentially a molecular ruler that works inside the fluid itself,” Friedler said. “We no longer need to immobilize fibrils on a surface or rely on large amounts of material. We can quantify fibril length directly in solution.”
Using submicroliter sample volumes, the team measured Tau fibrils ranging from as few as four molecular layers to more than 1,100 layers, even at nanomolar concentrations. The researchers said this level of sensitivity and resolution had not previously been achievable for amyloid fibrils in solution.
The new technique has immediate value for basic research into Alzheimer’s disease and related dementias. By allowing scientists to directly measure the length of Tau fibrils in solution, at very low concentrations and in complex biological mixtures, the method makes it possible to closely track how these toxic protein structures form, grow, and break apart over time. Researchers can now study the earliest stages of fibril development, compare fibrils from different diseases or patient samples, and observe how environmental conditions influence fibril behavior, all under conditions that more closely reflect what happens in the body.
Beyond basic research, the approach could also accelerate drug development and inform future diagnostics.
And in the longer term, “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,” Rüdiger said.
Friedler stressed that clinical use would require further development and validation.
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