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Diving Deeper Into the Mind – Unprecedented Insights Into the Brain’s Immune System
For the first time, the development process and characteristics of a particular type of brain immune cell have been properly documented, allowing for their proper identification amongst other immune cells.

After a century of modern neuroscience, humanity has made significant progress in understanding the body’s most complex organ, but many mysteries remain unsolved.

Fortunately, through the research efforts of Kyushu University’s Faculty of Pharmaceutical Sciences, a greater understanding of the brain’s immune system has been gained through the analysis of the development and genetic profile of the cells that comprise it.

The new insights, published in Nature, could help in research to decode the origins and mechanisms behind common neurodegenerative diseases like Alzheimer’s disease and multiple sclerosis.

“Many people are familiar with how neurons connect together to send signals across the brain, but there are also blood vessels that supply the brain with oxygen, and glial cells that act as the brain’s support network and immune system,” explained Takahiro Masuda, who led the study. “In fact, even the most generous estimates suggest only about half of the cells in our brains are neurons, so studying the other cells is just as vital for uncovering how the brain works.”

To broaden their understanding of the other non-neuronal cells in the brain, the research team had been studying the "central nervous system-associated macrophages", which are a subset of immune cells that protect the brain from infection. These macrophages have been hypothesised to have roles in the development of neurodegenerative diseases due to the protective effects they exert on the brain as immune cells.

Previous research has shown that there are many different types of brain-specific immune cells. In this study, the researchers focused their efforts on demystifying the macrophages surrounding blood vessels and those located in the meninges—the layers that surround the brain—known as “perivascular macrophages” and “meningeal macrophages”, respectively.

“Until now, these cells were not distinguished from other immune cells, and how and where these critical cells develop was significantly understudied,” continued Masuda. “So, we investigated fundamental characteristics of these cells, such as how to distinguish them from other cells in the brain, their exact locations, how they develop, what kind of genes they express, and how they interact with other cells.”

These central nervous system-associated macrophages, like the brain’s other immune cells, have their origins in the “yolk sac”, a structure found outside of the embryo during fetal development. As the development of the embryo progresses, the immune cells in the yolk sac migrate into the brain of the organism. By utilising a “fate-mapping” technique, the researchers managed to track the final location of the cells and discovered the processes that are responsible for the development of their final functions.

“We found that meningeal macrophages develop in the same way as other microglia and are formed during gestation. Perivascular macrophages, on the other hand, actually begin to form after birth and originate from the meningeal macrophages. This was very unexpected,” stated Masuda.

The team’s research also led to the discovery of the specific genes that are responsible for the generation of meningeal and perivascular macrophages.

“Identification of these genes will finally allow us to distinguish meningeal and perivascular macrophages from other microglia,” explained Masuda. “Now that we can study them individually, we can get a clearer picture of their functions.”

The findings will serve as important stepping stones to unlocking the deeper mysteries of the roles of the immune cells in the brain.

“Now that we know they are distinct, the next step is to figure out their functions. As their mechanisms are revealed, we hope to understand their role in pathologies like Alzheimer’s, autism spectrum disorder, and multiple sclerosis,” concluded Masuda.

Source: Masuda et al. (2022). Specification of CNS macrophage subsets occurs postnatally in defined niches.Nature, 604,740–748.

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