First direct measurement of dementia-linked proteins

Early detection of Alzheimer’s disease has come a step closer thanks to a new measurement method developed by chemists at Utrecht University. For the first time, they have made the growth of the notorious protein clumps involved in dementias such as Alzheimer’s, Parkinson’s, and Huntington’s directly measurable — even in blood. Chemists Françoise Dekker, Júlia Aragonès Pedrola, and Stefan Rüdiger are publishing their discovery today, together with international colleagues, in the journal PNAS.

The major problem with Alzheimer’s and other forms of dementia is that the disease begins long before it is detected or diagnosed. The first harmful processes that slowly but steadily damage the brain take place silently for years. Patients usually have no symptoms during that period. Meanwhile, the first harmful protein aggregates that eventually lead to dementia gradually build up.

With existing techniques, these early, hidden changes are almost impossible to detect. By the time memory loss and other symptoms appear, most of the damage has already been done. As a result, treatment usually starts too late or has little to no effect. This also makes the development of new medicines extremely difficult: by the time intervention begins, it’s already too late, and any potential effect is hard to measure.

“Paint” makes proteins measurable

With a new technique that effectively “paints” proteins, it is now possible to clearly visualise the very first, tiny protein clumps. It can even measure their length, which indicates how far the disease has progressed. This means the course of the disease could be tracked in detail.

A special ‘paint’ reveals and tracks the protein clumps behind dementia

The Utrecht chemists Françoise Dekker, Júlia Aragonès Pedrola, and Stefan Rüdiger developed the method together with colleagues from Utrecht University and other research institutes.

The method revolves around a family of molecules designed by Rüdiger’s team and their collaborators, called FibrilPaint. These molecules bind exclusively to the long, thread-like protein structures that accumulate in the brains of dementia patients. These structures are known as amyloid fibrils.
 

Directly measurable

FibrilPaint is also fluorescent: it emits light when studied with special measuring equipment. In this way, it reveals the size of the fibrils, from the very first, tiny clumps to fully developed structures. A major advantage is that blood or cerebrospinal fluid from patients can be assessed directly, whereas normally, extensive pre-treatment steps are required to reliably measure proteins.

We can now track the growth of fibrils step by step using FibrilPaint.

“We could already see such fibrils under an electron microscope, but this method is not suitable to monitor body fluids” says Stefan Rüdiger, Professor of Protein Chemistry of Disease at Utrecht University. “With FibrilPaint, we can now follow their growth step by step in liquid form.”

Medicines against dementia

The researchers expect FibrilPaint to help improve the development of dementia drugs. “With our technique, we will soon be able to monitor the progression of the disease much more precisely and determine whether a treatment is effective,” says Dekker. The team has already founded a start-up called NeuroTidal Diagnostics to bring FibrilPaint into practical use. This will allow them to contribute to clinical trials of dementia medications.

Our technique will eventually allow us to follow the course of the disease much more accurately and see whether a treatment really works.

Too ambitious?

For Rüdiger, this is also a personal milestone. “Three years ago, I described the idea for FibrilPaint when applying for a major research grant. It was rejected at the time for being too ambitious. But I persevered and sought other ways to develop FibrilPaint. Reaching this point now feels like a real milestone.”

The development of FibrilPaint is the result of close collaboration between Utrecht researchers and international partners. Among the supporters of this research were the charities Alzheimer Nederland and the Campagneteam Huntington, and the Dutch Gravitation Programme FLOW.