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The cleaning cells of the brain

Scientists from the Weizmann Institute have discovered a group of immune cells whose measured activation may underlie future treatment of Alzheimer's disease

Diagram showing the new set of findings. The discoveries mark a possible new target for the treatment of Alzheimer's disease. Source: Weizmann Institute magazine.
Diagram showing the new set of findings. The discoveries mark a possible new target for the treatment of Alzheimer's disease. Source: Weizmann Institute magazine.

In Alzheimer's disease, pathological processes occur that cause a significant reduction in brain function. Inside the brain cells, and between them, accumulates amyloid-beta protein ("plaques"), which are supposed to be eliminated. In addition, the skeletal proteins of nerve cell extensions lose their normal structure, which impairs their function and causes their death. Also, the neural communication nodes (synapses) weaken, both due to structural changes, and due to the weakening of chemical communication pathways.

A central question in the field of degenerative brain diseases is why immune cells, which are permanently present in the brain and are called microglia, do not come into action and repair the damage? The microglial cells are supposed to break down and remove cell fragments and various substances that do not function properly. However, the activity of these cells is done under strict control, to allow them to eliminate waste without damaging the healthy nerve cells that store important information. This range, between necessary immune activity and the danger that overactivity will damage healthy nerve cells, meant that these cells were attributed a negative effect in every case of local inflammation that develops in neurodegenerative diseases such as Alzheimer's and others.

This concept led many scientists to interpret the phenomenon of local inflammation in the brain, which accompanies Alzheimer's disease, as a negative phenomenon caused by an overly aggressive activity of the microglial cells, which results from a malfunction in their regulatory mechanisms, or from an uncontrolled entry of immune cells from the blood into the brain. Therefore, anti-inflammatory treatments have been tried in this area. These experiments were not successful and left the scientists in the field with the question of the function of the immune cells in neurodegenerative diseases of the brain.

Prof. Michal Schwartz from the Department of Neurobiology at the Weizmann Institute, has shown over the years that the recruitment of cells from the peripheral immune system is not only harmless, but also helpful in dealing with Alzheimer's disease - provided it is controlled. And so the question of the role of the brain's own immune cells, the microglial cells, remained open: are they helpful? useless? Or pests?

Prof. Schwartz together with Prof. Ido colleague From the Department of Immunology at the Weizmann Institute, and the members of their research groups, the post-doctoral researchers Dr. Hadas Keren Shaul and Dr. Asaf Weiner, and the research students Amit Spinard, Orit Matkovitz and Raz Dvir, now offer an answer to this question, along with a new research direction for the development of ways to treat the disease .

This is a new concept in understanding how to deal with Alzheimer's disease, based on an understanding of the central role of the microglial cells in the disease, and on the insight that the restraint mechanisms of these cells, which are important for normal functioning, become an obstacle in the patient's brain."

Bottom row (from right): Dr. Hadas Keren Shaul, Prof. Michal Schwartz, Prof. Ido Amit. Top row (from right): Amit Spinard, Orit Matkovits-Nathan, Dr. Assaf Viner. Source: Weizmann Institute magazine.
Bottom row (from right): Dr. Hadas Keren Shaul, Prof. Michal Schwartz, Prof. Ido Amit. Top row (from right): Amit Spinard, Orit Matkovits-Nathan, Dr. Assaf Viner. Source: Weizmann Institute magazine.

The scientists examined genetically modified mice, which are a research model for Alzheimer's disease and whose genetic load includes five mutant human genes, which are among the genetic factors identified as responsible for the development of the disease. In the brains of these mice, phenomena occur similar to those that occur in Alzheimer's disease in humans. A significant obstacle in understanding the roles of immune cells in Alzheimer's disease, and in other degenerative brain diseases, is the ability to accurately separate apparently similar cells, with different functions, and hence, to understand who is "friend" and who is "enemy". The scientists used an advanced technology of sequencing the genetic material of individual cells, a kind of "genetic microscope", developed in recent years in Prof. Amit's laboratory, which allows full genetic sequencing of individual cells to be performed - thus identifying the unique function of immune cells, even if they are rare.

In this study, the scientists sequenced the RNA content of all the immune cells in the brains of the experimental mice (a process that was impossible to perform until very recently). They repeated this sequencing process, at different time points, throughout all stages of the disease's development, and compared the results to healthy control mice. In this way, they were able to identify a subset of unique microglial cells, which are not found in healthy mice, and which change gradually, as the disease progresses. These cells were called disease-associated microglia (DAM). Later in the study, it was found that these cells express proteins that identify the damage products caused by Alzheimer's disease, and break down the "plaques".

It was also found that the development of these unique cells depends on two mechanisms: a reduction in the expression of the control proteins (checkpoints) that restrain the activity of microglia in the healthy brain, and the activation of a protein structure that detects the accumulation of foreign lipids (fat-like molecules) and dead cells, including a protein called TREM2. In Alzheimer's patients, a mutation in this protein is accompanied by a disease that develops earlier and in a more turbulent manner. When the scientists isolated microglial cells from the brains of Alzheimer's model mice that had been engineered so that they could not express TREM2 (this work was carried out in collaboration with Prof. Marco Colonna from St. Louis University), the microglial cells failed to develop into DAM cells and eliminate the "plaques". Examining the brains of Alzheimer's model mice, as well as of humans who suffered from Alzheimer's, it was found that those unique cells are located close to the "plaque" areas, which indicates the connection between their activation mechanism and their activity. In fact, these unique cells express proteins that were previously diagnosed in Alzheimer's patients as "risk proteins" in the disease. In other words, these cells express proteins whose mutations cause the cells to malfunction, and are therefore accompanied by a more severe disease.

"This array of findings", says Prof. Amit, "leads us to the understanding that reducing the expression of the restriction proteins is necessary for a sufficient increase in the activation pathways of the unique cells we identified, so that they can perform the job of removing the plaque."

Prof. Schwartz adds: "This is a new concept in understanding how to deal with Alzheimer's disease, based on an understanding of the central role of the microglial cells in the disease, and on the insight that the microglial cell checkpoints, which are important for normal functioning, become an obstacle in the patient's brain."

These discoveries mark a new possible target for the treatment of the disease: a drug that may be developed in the future, and which will reduce the expression of the control proteins in the unique group of cells that the scientists identified; You will increase the expression of the repair pathways - something that may accelerate the development process of these cells, and increase their efficiency in removing "plaque" from the brain - and thus possibly reduce various symptoms of the disease.

Adds the post-doctoral researcher Dr. Hadas Karen Shaul, who was one of the leaders of the research: "At this stage we are investigating different ways to optimally activate the microglial cells." This challenge is at the center of the current research of these research groups.

One response

  1. If we think of a brain with Alzheimer's as a city completely clogged with garbage that is partly organic and partly plastic.
    So microglia are a combination of scavengers and a garbage truck that run in the microcosm that we have in the brain.
    The role of Alzheimer's treatment is great for them. Because garbage they eat and plastic they keep. When they fill up with garbage they park on the side and do more harm than good.

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