Immune cells of the brain are not all the same – new research could open novel therapeutic pathways

Newswise — A new study in Nature Neuroscience shows that the immune cells in the brain, called microglia, are not all identical as previously thought. Scientists discovered a special group of microglia with distinct characteristics and roles that play a crucial role in ensuring the brain functions properly in mice. Similar microglial subsets have also been found in humans, which is really exciting because it suggests new potential treatments could be developed.

Scientists from the University of Helsinki, Karolinska Institutet, and the University of Seville worked together to study a specific group of microglial cells called ARG1+microglia. These microglial cells produce an enzyme called arginase-1 (ARG1). Through advanced imaging methods, the researchers discovered that ARG1+microglia are present in large numbers during brain development but are less common in adult animals. Interestingly, these ARG1+microglia are found in specific areas of the brain that are crucial for cognitive functions like learning, thinking, and memory.

Dr. Vassilis Stratoulias, a Senior Researcher at the University of Helsinki and the lead author of the study, explains that cognition and memory play important roles in human characteristics. Microglia are essential for the healthy development and functioning of the brain. Unfortunately, cognitive decline is frequently observed in neurodegenerative and psychiatric disorders such as Alzheimer's and Parkinson's disease, schizophrenia, and depression.

Dr. Mikko Airavaara, a co-author of the study from the University of Helsinki, emphasizes that microglia are implicated in almost all brain-related diseases. This makes them promising targets for new drugs and innovative treatment strategies. By gaining a deeper understanding of the basic biology of microglial cells, researchers can explore new avenues for drug development, aiming to address currently untreatable brain diseases.

Abnormal behavior reveals cognitive deficits

The study revealed that mice that lacked the microglial protein ARG1 showed reduced interest in exploring unfamiliar environments. This abnormal behavior in rodents is associated with cognitive impairments, particularly in the hippocampus, which is a crucial brain region responsible for learning and memory.

The researchers did not observe any noticeable differences in the physical shape of ARG1+microglia compared to nearby microglia that do not produce ARG1. This may explain why these specific microglia have not been extensively studied in the past. However, by utilizing a technology that enables the comparison of RNA profiles between different cell populations, the researchers discovered significant molecular differences between ARG1+microglia and neighboring microglia that do not express ARG1. This suggests that these microglia have unique characteristics at the molecular level.

The study also revealed an interesting finding related to the impact of ARG1 microglial deficiency on behavioral and hippocampal impairments. Female animals exhibited more prominent impairments compared to males. This observation is significant because there is a sex bias in many diseases, including Alzheimer's disease. In fact, women are more likely than men to develop Alzheimer's disease, which is a common neurodegenerative disorder that severely affects cognitive abilities. In recent years, microglia have been recognized as key contributors to Alzheimer's disease. Therefore, the findings of this study have relevance to understanding and potentially treating this disease. While further research is needed to establish a direct link between a specific microglial subset and Alzheimer's disease, this study offers a new perspective through which we can view Alzheimer's disease, as well as other brain disorders. It also opens up new possibilities for therapeutic interventions.

Dr. Bertrand Joseph, Professor at Karolinska Institutet and senior author says:

“In addition to offering better understanding of brain development and the contribution of microglial diversity to that, the study could provide new clues about how to manage neurodevelopmental disorders or neurodegenerative disorders presenting a cognitive component and often differences between males and females.”