A recent study published in Nature Neuroscience shows that, contrary to popular belief, the brain’s immune cells, known as microglia, are not all the same.
The researchers found that a unique microglial subset with unique features and functions is important for establishing proper cognitive function in mice. Evidence for such a microglial subset exists for the human brain as well, opening up new possibilities for novel therapies.
An international collaboration, led by researchers from the University of Helsinki (Finland), Karolinska Institutet (Sweden) and the University of Seville (Spain) characterized ARG1+microglia, a subset of microglial cells, which produce an enzyme called arginase-1 (ARG1).
Using advanced imaging techniques, the team found that ARG1+ microglia were abundant during development and less prevalent in adult animals. These ARG1+ microglia are located in certain areas of the brain that are important for cognitive functions such as learning, thinking, and remembering.
“Cognition and memory are important components of what makes us human, and microglia are necessary for proper brain development and function. Cognitive decline is a common feature of neurodegenerative and psychiatric conditions such as Alzheimer’s and Parkinson’s diseases, schizophrenia and depression,” said Vassilis Stratoulias, senior researcher at the University of Helsinki and lead author of the study.
“Microglia are implicated in almost all brain pathologies, making them prime candidates for new drug targets and innovative therapeutic approaches. Understanding the basic biology of these cells will be a way to generate new directions for drug development to treat currently incurable brain diseases,” added co-author Mikko Airavaara from the University of Helsinki.
Abnormal behavior reveals cognitive deficits
The researchers found that mice lacking the microglial protein ARG1 were less willing to explore new environments. This abnormal rodent behavior is linked to cognitive deficits and, more specifically, disturbances in the hippocampus, a part of the brain important for learning and memory.
The investigators were unable to identify differences in the shape of ARG1+ microglia when compared to neighboring microglia that do not express ARG1, suggesting a reason why these microglia have not been studied before. Using technology that allows comparison of RNA profiles between cell populations, ARG1+ microglia were found to differ significantly from their neighboring ARG1-negative microglia at the molecular level.
Another key finding of this study was that the female animals displayed more pronounced hippocampal and behavioral disturbances caused by ARG1 microglial deficiency. Sex bias is present in many diseases including Alzheimer’s disease.
Women are more likely than men to suffer from Alzheimer’s disease. Microglia have emerged as key players in Alzheimer’s disease in recent years, making the findings of this study relevant to this disease. Although the scientists say more research is needed to demonstrate a link between Alzheimer’s disease and specific microglial subsets, they note that this study could “provide a new prism through which we look at Alzheimer’s disease specifically – and brain disease in general – and open up new therapeutic pathways.” ”
Bertrand Joseph, professor at Karolinska Institutet and senior author, said: “As well as offering a better understanding of brain development and the contribution of microglial diversity, this research may provide new clues about how to manage neurodevelopmental disorders or neurodegenerative disorders that present cognitive impairment. components and often differences between men and women.”
Last year, a major step forward in the treatment of Alzheimer’s was hailed when a drug being tested, lecanemab, demonstrated a reduction in disease in the brain while slowing memory decline.