In the immune system the 'direction' of memories. An Italian-led study reveals that the brain cells of the microglia, the bulwark that defends the central nervous system from attack by external enemies, trauma or infections, also have the task of guiding the development and maturation of the areas of the hippocampus responsible for to memory. And they do this by modifying the metabolism of the neurons that make up these areas. The research, published in 'Immunity', is coordinated by Michela Matteoli, full professor of Pharmacology at Humanitas University and director of the Neuroscience Program of the Irccs Humanitas Clinical Institute on the outskirts of Milan. The work adds “a new piece to the puzzle on the complex relationship between immunity and the nervous system”, a card that “could change our approach to various neurodevelopmental and neurodegenerative diseases, including Alzheimer's”is the hope of the authors.
“We discovered – says Matteoli – that if the microglial receptor Trem2 does not function correctly, memory neurons in the hippocampus present anomalies in their energy metabolism during development, with implications that continue over time. The discovery is exciting not only because reveals an unprecedented function of microglial cells, but because we know that defects in the metabolism of neurons in this area are involved in various neurodegenerative diseases, including Alzheimer's.The fact that mutations in Trem2 constitute a risk factor for the onset of the disease, as demonstrated some years ago by genetic screening studies on patients, suggests the relevance of this process”.
The preclinical study was conducted in collaboration with the group of Simona Lodato, head of the Humanitas Neurodevelopment Laboratory and professor of Histology and Embryology at Humanitas University, Katia Cortese of the University of Genoa and Rafael Arguello of the National Research Center scientific research (Cnrs) of Marseille, France. Among the funding that made it possible was an ERC Advanced Grant obtained by Matteoli in 2022 from the European Research Council and a postdoc scholarship from the HiPPO program of the Humanitas Foundation for research, which supported the work of Erica Tagliatti, first author of article together with Genni Desiato.
In recent years – they explain from Humanitas – the idea of the brain as a privileged organ from an immunological point of view, isolated from the rest of the organism, has been revolutionized. Today we know that starting from the early stages of development up to aging, the continuous dialogue between nerve cells and immune cells guarantees the functioning of the brain and that its alterations are indeed involved in multiple diseases. The absolute protagonists of this continuous interaction are the microglial cells, the immune cells that reside in the brain, and in particular their receptor called Trem2, involved in many processes and identified already in 2013 because when mutated it increases the risk of developing dementia and Alzheimer's.
The mechanism at the origin of the link between defective versions of Trem2 and the onset of Alzheimer's is still being studied. Finding out could pave the way for the development of new therapeutic approaches for the disease, which is still without effective treatments. The new work, although limited to experimental models, is considered relevant because it reveals an unprecedented role of Trem2 in the formation and functioning of the areas that govern memory, those most affected by Alzheimer's disease.
“According to the results obtained in the laboratory – illustrate Tagliatti and Desiato – in the absence of Trem2 the neurons that make up the memory area in the hippocampus not only develop late, but present transcription and behavioral anomalies that persist over time, especially of a metabolic type: if Trem2 is missing in microglia, the mitochondria of neurons, which are the true 'energy centers' of cells, are fewer in number and have a reduced structure and functionality. For the first time we have demonstrated that cells of microglia and their receptor Trem2 have a role in controlling the maturation of memory neurons and above all their metabolic profile”.
The discovery was therefore conducted in the laboratory and on preclinical models “further research will be necessary to understand its real implications in the study of diseases such as dementia and Alzheimer's”, Humanitas specifies. But for scientists “there are many avenues open. Patients with genetic variants of Trem2 could in fact have metabolism problems in the area of the brain responsible for memory, problems that could weaken the area and make it more susceptible to neurodegeneration. Not only that The metabolic impact of Trem2 deficiency, observed during development, may recur in later life, when we know that levels of the receptor decline physiologically.”
“This research – comments Matteoli – demonstrates once again that in the brain, development and aging are two sides of the same coin and should be studied jointly. In recent years, for example, it has been discovered that some proteins implicated in neurodegenerative disorders play an important role already during the development of the brain. Dysfunctional processes affecting these proteins during development can therefore produce long-term effects, also because they affect a tissue, such as nervous tissue, which does not undergo the continuous cellular renewal observed in other organs of the body”.
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