Alzheimer’s disease, which affects around a million people in France, is characterized by the accumulation of amyloid protein plaques in the brain, and tau proteins in the neurons themselves, making them the main therapeutic targets. . In the magazine Molecular Psychiatry of June 14, a French team describes how, in mice, it was possible to partially block this mechanism by exploiting a discovery made in 2012 by an Icelandic team.
By analyzing the entire genome of 1,795 Icelanders, Thorlakur Jonsson (deCODE genetics, Reykjavik) and his colleagues identified a mutation present in certain inhabitants of the island, which had a protective effect against this neurodegenerative disease , but also normal neurocognitive decline. This mutation, called “A673T”, found in less than 1% of Scandinavian populations, is located on a gene coding for an amyloid precursor protein (APP).
Alzheimer’s disease is sometimes considered according to the model of prion diseases, where a protein with an abnormal conformation gradually induces this same three-dimensional structure and ends up forming deleterious aggregates. At the Neurodegenerative Diseases Laboratory in Fontenay-aux-Roses (Hauts-de-Seine), Marc Dhenain (CNRS, CEA) is working on this “pseudo-prion” hypothesis, with the idea that certain APPs trigger this domino mechanism. “Some strains, like the one from Osaka, are very toxicexplains the researcher. We hypothesized that, conversely, others, such as the Icelandic strain, would have a protective effect. »
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The amyloid cascade hypothesis
To prove it, he and his colleagues injected a peptide, a small molecule derived from APP, carrying the famous A673T mutation, into the hippocampus of transgenic mice designed to mimic Alzheimer’s disease. The hippocampus is a small brain structure very involved in memory. “The effect on amyloid accumulation was mixed, but we observed a reduction in inflammation, tau protein accumulation, damage to the connections between neurons – synapses – and cognitive impairment. », lists Marc Dhenain. Memory, in particular, was protected. A single injection produced such an effect for four months, according to the publication, “but we have now seen it for nine months, which is quite astonishing”.
How to transfer these results to humans? At Laval University (Quebec), Jacques Tremblay was already working on a gene therapy using molecular scissors of the Crispr-Cas9 type in order to introduce the beneficial Icelandic mutation in situ, into the genome of neurons. “This important new publication encourages me to continue on this path”he notices, saying to himself ” surprised “ by the duration of the beneficial effect induced by a single injection of peptides.
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