A key to detecting Alzheimer's disease with certainty

A key to detecting Alzheimer's disease with certainty

(UCLouvain press release [FR])

A team of scientists from the de Duve Institute and the Institute of Neuroscience at UCLouvain, led by Professor Bernard Hanseeuw, has just uncovered a lead that opens up prospects for a more reliable ante-mortem diagnosis, as well as possible new treatments. The study is published in Nature Communications.

In a nutshell:

• Alzheimer's disease is currently distinguished from other neurodegenerative diseases involving the tau protein on the basis of symptoms, but this diagnosis is not totally reliable. Only an autopsy can confirm with certainty which disease it is.
• Researchers at UCLouvain's Institute of Neuroscience and the de Duve Institute have compared aggregated tau protein (which has been the focus of attention for 30 years) with the same soluble protein, which could be characterised while patients are still alive by means of a lumbar puncture (feasible as of now) or a blood test (in the future).
• They have discovered that it is the changes in the protein, once it has been produced, that could be the key to the development of one neurodegenerative disease or another.

The team behind the discovery From left to right: Gaëtan Herinckx, Mark Rider, Nathalie Kyalu Ngoie Zola, Didier Vertommen (de Duve Institute) et Bernard Hanseeuw (Institute of Neuroscience)

For years, scientists trying to gain a better understanding of Alzheimer's disease or other neurodegenerative disorders - tauopathies, since they involve the tau protein - have come up against a difficulty: how to diagnose the disease 'before' in a completely reliable way, since today only autopsy can describe the aggregates of tau protein in the brain and therefore know with certainty what type of neurodegenerative disease the person was suffering from.

The clinician can, on the basis of the symptoms - which depend on the brain regions affected - determine which pathology is involved. However, the disease sometimes develops in unusual areas of the brain, leading to misdiagnosis. Diagnosis is crucial, because treatment depends on the pathology.

A team of scientists from the de Duve Institute and the Institute of Neuroscience at UCLouvain, led by Professor Bernard Hanseeuw, has just uncovered a lead that opens up prospects for a more reliable ante-mortem diagnosis, as well as possible new treatments. The study is published in Nature Communications.

Researchers have known for a long time that the tau protein exists in different types of isoforms*, some of which are a little longer, others a little shorter. In Alzheimer's disease, all the isoforms are affected and aggregate. In other tauopathies, it is either the so-called 4R isoforms or the 3R isoforms that accumulate.

"For years, explains Professor Bernard Hanseeuw, we've been trying to measure these isoforms in the cerebrospinal fluid taken from patients by lumbar puncture, but we haven't succeeded. Why not? Because in this fluid, we don't observe any differences in isoforms between tauopathies". However, in the aggregated protein taken at autopsy, the 3R and 4R isoforms are clearly distinguishable. This is what the scientific literature has been describing for 30 years.

Researchers at the Institute of Neuroscience (IoNS) had the idea of exploring another avenue with the help of a powerful tool available at UCLouvain's de Duve Institute, mass spectrometry, which is capable of characterising proteins. Working on cerebral autopsy material, they focused on what are known as 'post-translational' modifications, i.e. modifications that affect any protein produced. By checking all the modifications, on the one hand to the soluble protein, and on the other to the aggregated protein**, they discovered that modifications to the soluble protein determine the type of isoforms that aggregate and therefore preside over the type of disease from a biochemical point of view.

For the scientists, these 'post-translational' modifications to the soluble protein are a great encouragement to continue with this research, this time on cerebrospinal fluid, which can be taken directly from the patient in order to determine ante mortem the type of aggregates that form in the brain and to attempt to treat the pathology that has been correctly identified.

Bernard Hanseeuw emphasises that the originality of the work lies in the comparison between the soluble protein and the aggregates, whereas most biochemists work on the aggregates, which are visible under the microscope. "On a more fundamental level, explains the researcher, this comparison provides a better understanding of the aggregation process. Our hypothesis is that the modifications found only on the aggregated protein... probably cause the aggregation. And those found only on the soluble protein probably prevent aggregation. This opens up avenues for developing a biomarker, and therefore a diagnosis, but also for pinpointing the modifications that cause this protein to aggregate or not, in other words a great therapeutic avenue".

"This result confirms that the problem with neurodegenerative diseases is not the production of these proteins, because they are produced normally. The problem is the elimination or modification of these proteins once they have been produced".

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* The function of the tau protein is to stabilise microtubules, and therefore the electrical wiring of neurons, named axon. The 4Rs, slightly longer isoforms, bind the microtubule more, resulting in more stable neurons. The 3Rs bind it a little less well, resulting in neurons that are a little more flexible. For example, the human foetus has only 3Rs, which means a great deal of flexibility and less stability. Isoforms are variants of the same protein, changing by a few amino acids.

** The scientists extracted the tau protein from brain extracts, separated the aggregates from the soluble fraction of the brain (the interstitial fluid and the cerebral intracellular fluid) and analysed the aggregated tau protein and the soluble tau protein separately. In cerebrospinal fluid collected by lumbar puncture, only soluble tau protein can be obtained.

Article describing this research

Specific post-translational modifications of soluble tau protein distinguishes Alzheimer's disease and primary tauopathies.

Kyalu Ngoie Zola N*, Balty C*, Pyr dit Ruys S, Vanparys AAT, Huyghe NDG, Herinckx G, Johanns M, Boyer E, Kienlen-Campard P, Rider MH, Vertommen D**, Hanseeuw BJ**. (* co-first and ** co-last authors)

Nat Commun. 2023, 14(1):3706. 

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Euro.dayfr.com - A surer diagnosis of Alzheimer’s disease during the patient’s lifetime: UCLouvain researchers find a new lead - 27/07/2023
BrusselsTimes.com - Belgian scientists make new advances in Alzheimer’s research - 29/07/2023
Euro.dayfr.com - How to Solve the Alzheimer’s Riddle: Recent Encouraging Advances - 03/08/2023
FocusOnBelgium.be - On the way to a more reliable diagnosis of Alzheimer's disease - 24/08/2023

It.dayfr.com - Una diagnosi più sicura della malattia di Alzheimer durante la vita del paziente: i ricercatori dell’UCLouvain trovano una nuova pista - 27/07/2023

Also on TheWorldNews.net (FR), DHnet.be (FR), LeSpecialiste.be(FR), Medi-Sphere.be (FR), Medi-Sfeer.be (NL)

Funding

This research is supported by the WEL Research Institute (Welbio), the FNRS, the Queen Elisabeth Medical Foundation and a Concerted Research Action (FWB).