Will we ever be able to protect ourselves from Alzheimer’s? A glimmer of hope could well appear thanks to a French study by the CNRS and the University of Grenoble Alpes carried out on mice in the laboratory. This work is published on June 14, 2024 in the journal Molecular Psychiatry. Neurobiologists have inoculated a protein present in a mutated form in the genome of Icelanders, who are particularly resistant to cognitive decline. They found that after just one injection, the treated mice did not develop any symptoms of Alzheimer’s disease.
Alzheimer’s disease is the result of brain degeneration, caused by the abnormal accumulation of amyloid beta (or β-amyloid) and Tau proteins in the brain. However, for several years, the scientific community has believed that the toxicity of β-amyloid proteins at the level of synapses – the areas where connections between neurons are established – could be responsible for neurofibrillary degeneration linked to a dysregulation of the functions of Tau proteins. This is why French researchers have been mainly interested in β-amyloid proteins, and more particularly in those of the pseudo-prion type.
Alzheimer: a pseudo-prion disease
A prion-like protein is a protein that, if its conformation changes, can become pathogenic and transmit this character to surrounding normal proteins. This is the case for example in the context of Creutzfeldt-Jacob disease. “Previously, it was not thought that degenerative diseases could be of the prion type. But for around ten years, we have known that the proteins involved in Alzheimer’s disease behave like prions inside the body. This is why we speak of pseudo-prions, especially since they are much less transmissible than prions”explains Marc Dhenain, researcher at the neurodegenerative diseases laboratory (CNRS, CEA, Paris-Saclay University), and co-senior author of the study.
Be careful, however: neurodegenerative diseases are in no way transmitted between individuals, but inoculation of a pathogenic pseudo-prion in the laboratory can actually lead to the onset of Alzheimer’s disease. On this basis, Marc Dhenain and his colleagues looked for a way to slow down the action of these pseudo-prions.
An ‘Icelandic mutation’ prevents the onset of the disease
Their research took them… to Iceland. The small population of the island – some 300,000 inhabitants – made genotyping of the entire country possible. However, this census revealed a mutation in a precursor of β-amyloid proteins. By tracking the cognitive level of these people, researchers found that they were protected against Alzheimer’s disease. How is such protection possible?
One hypothesis is that the mutation observed in the Icelandic genome slows down the uncontrolled production of β-amyloid proteins. Based on this conjecture, French neurobiologists inoculated this mutation into mice modified to contract Alzheimer’s disease, and found that those who had received an injection retained their memory for the following months.
Scientists appreciated the memory of mice thanks to Morris’s swimming pool experiment: “It’s a system where animals are put in a pool and have to find their way back to a platform. When memory weakened, the mice did not find this path, while the treated mice still remembered it four months later.summarizes Marc Dhenain.
Brain slices that have been stained to detect Alzheimer’s disease lesions.
Protect synapses by reducing toxicity
But that’s not all. With his team, he introduced more or less toxic forms of amyloids into the brains of mice. Result: the mutation also seems to reduce the damage caused to synapses. “What’s really incredible is that we’re not used to a single injection still showing results after four months. This is explained by the fact that there is a process of protein amplification once the mutated protein has been inoculated.rejoices Marc Dhenain.
The next step will be to transmit this amyloid form to humans. A project to be viewed in the long term because no clinical trial can be considered for at least five years.
By Marine Laplace
Opening image: Alzheimer’s Tau lesions in green surrounding an amyloid lesion (large blue area). The red elements are brain cells. The other blue elements are cell nuclei.
Credits: Fanny PETIT
