Wir überwinden Grenzen

New method enables precise research into parts of immune cells in the brain that have hardly been studied to date / Findings can help to better understand learning processes and diseases such as Alzheimer's and brain tumors and to develop new therapies

Immune cells called microglia play a central role in cleaning the brain. In healthy and diseased brains, the restless scavenger cells collect the constantly accumulating waste and process it further in their "stomachs", the phagosomes. Researchers at the Medical Center - University of Freiburg have now developed an innovative method together with US colleagues to precisely analyze these cell components, which have been little researched to date. It enables rapid and functional analysis of phagosomes. This has already enabled them to gain initial important insights into their functions, which offer clues to new therapeutic approaches for neurodegenerative diseases and brain tumors. The results of the study were published in the journal Immunity on August 15, 2024.

"We have developed a completely new method that can be used to precisely sample and examine phagosomes in human cells," says first author Dr. Emile Wogram, physician and scientist at the Institute of Neuropathology at the Medical Center - University of Freiburg. Prof. Dr. Marco Prinz, Medical Director of the Institute of Neuropathology at the Medical Center - University of Freiburg, adds. "This will help us to better understand diseases such as Alzheimer's or brain tumors and to develop new therapeutic approaches."

Central role in cleaning and maintaining the brain

Microglia cells are at the forefront of the brain's immune defense. For example, they eliminate invading bacteria by enveloping them and processing them in their "stomachs", the phagosomes. These phagosomes act as a kind of "waste recycling" by breaking down the enveloped intruders with the help of digestive enzymes. Dead endogenous cells or cell components are also removed and recycled daily by the phagocytes in the healthy brain. Scientists agree that cellular waste disposal plays an important role in brain development, in the healthy brain, but also in diseases such as Alzheimer's and brain tumors.

A "simple" method brings success

Until now, it had not been possible to remove the very unstable phagosomes from the phagocytes in a functional state and examine them. Wogram therefore began developing a new method for scavenger cells in cell culture at the Whitehead Institute for Biomedical Research, Cambridge, USA, in the laboratory of Prof. Rudolf Jaenisch, which he then further developed in Freiburg to also analyze phagosomes in human brain samples.

The method is as simple as it is elegant: in the first step, the phagocytes are opened and the phagosomes are bound to magnetic beads with antibodies. In the second step, the bound beads together with the phagosomes are isolated with a magnet, washed and finally analyzed. "The whole process takes just half an hour, which is crucial to ensure that the phagosomes remain intact and their contents are not digested before analysis," says Wogram.

Link to tumor growth and Alzheimer's disease

"We have already been able to show with the new method that, in addition to removing cell debris and Alzheimer's plaques, the phagosomes also remove superfluous or damaged connections between nerve cells. For the first time, we were able to understand exactly which structures are degraded," says Wogram. This opens up new ways to better understand the role of these cells in learning processes and diseases such as Alzheimer's.

The new method also enabled the researchers to measure differences between phagosomes in healthy tissues and in tumor tissues. They found that phagosomes in tumor tissues contained unusually high amounts of quinolinic acid, which can be used for metabolism in the brain but can also damage nerve cells.

"The exciting thing here is that phagocytes in the brain are the only cells that can produce quinolinic acid and store or break it down in the phagosome. While quinolinic acid can damage nerve cells in Alzheimer's disease, it presumably promotes the growth and spread of brain tumors," says Wogram.

The phagosome therefore has an important role to play: it can influence the course or even the development of incurable brain diseases. "As soon as we better understand how phagosomes control the redistribution of quinolinic acid, this may provide us with a new starting point for the treatment of Alzheimer's or brain tumors," says Wogram.

Original title of the publication: Rapid phagosome isolation enables unbiased multiomic analysis of human microglia phagosomes
DOI: 10.1016/j.immuni.2024.07.019
Link to the study:https://www.cell.com/immunity/fulltext/S1074-7613(24)00368-6