Biotechnology

Very long protein fibrils may aid in the early diagnosis of Alzheimer’s

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Early diagnosis and treatment of dementia such as Alzheimer’s disease is still a big challenge.

It is known that certain proteins in the cerebrospinal fluid can be used to diagnose Alzheimer’s disease. However, the current detection methods for these biomarkers through biochemical tests can only confirm and quantify the presence of these pathological proteins. No conclusions can be drawn about the native morphology of their proteins using biochemical assays, which retain information about disease stage.

However, such information, when obtained in a direct, off-label manner, can enable conclusions to be drawn about the stage of the disease and evaluate the efficiency of the prescribed treatment. A team from the Transport at Nanoscale Interfaces Laboratory in Empa and the Department of Neurology at Cantonal Hospital in St. Gallen, Switzerland, has now used atomic force microscopy (AFM) to visualize proteins that indicate Alzheimer’s disease in as close to reality as possible. The researchers recently published their results in the journal Communications Biology.

Molecules in natural form

With this new study, the researchers say they have added another piece of the puzzle to their insights about Alzheimer’s development and diagnosis. In previous studies, a team led by researcher Empa Peter Nirmalraj of Transport at the Nanoscale Interface laboratory in Dübendorf have been able to uncover potentially pathological proteins in their natural form in blood. Now, the researchers show in detail, the protein forms unchanged directly in the spinal fluid.

Impressive precision

This is possible thanks to AFM. Reminiscent in size of conventional table-top microscopes, AFM technology allows morphological observations in the nanometer range without damaging proteins. And in analyzing differences in size, structure, shape, and assembly patterns of proteins accumulating directly in spinal fluid, the team has now been able to identify links to disease stage.

“While only short protein fibrils, around 100 nanometers in length, are found in people in the early stages of the disease, fibrils with multiples of these lengths – reaching several micrometers – appear in the later stages of the disease,” said biophysicist Nirmalraj.

In contrast, in cognitively healthy individuals, there were no fibrils, or even shorter fibrils in the spinal fluid samples.

After this pilot study with 33 people, the team will now increase efforts to match the findings collected in the laboratory with data from a larger group of patients and gain information about the chemical properties of proteins in body fluids. Recently, Nirmalraj received support from Dementia Research Synapsis Foundation Switzerland, to further advance the ongoing studies for the early detection of blood-based Alzheimer’s disease.

“AFM technology has the potential to complement conventional biomarker tests and improve early detection of Alzheimer’s,” said Nirmalraj.

This is because while biomarker tests show protein levels, AFM technology can provide information about differences in the morphology of protein aggregates, which reflect disease progression, he said.

In addition, it will make it possible to further investigate disease processes to provide the basis for new, more effective drugs.

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