Friend and foe
In search of the molecular root causes of Alzheimer's disease, researchers at the University of Washington, working under the guidance of Professor David Holtzman, have identified a very interesting mechanism that, depending on the conditions, contributes to the development of the disease or protects the brain from damage. The main element of this mechanism is the TREM2 gene, mutations of which can significantly increase the risk of developing Alzheimer's disease in humans. In the early stages of the disease, variants of the TREM2 gene associated with a high risk of its development reduce the ability of the immune system to protect brain cells from toxic beta-amyloid.
On the other hand, it turned out that at later stages, when the brain tissue is already dotted with toxic accumulations of another protein characteristic of Alzheimer's disease, known as tau protein (tau), the absence of the TREM2 gene protein product in the body protects the brain from damage.
Beta-amyloid plaques begin to form in the brains of Alzheimer's patients years before the onset of characteristic symptoms, such as memory impairment and confusion. Apparently, the amyloid plaques themselves do practically no harm, since many people retain a clear consciousness even if there are a large number of them in the brain. However, the presence of clusters of beta-amyloid increases the risk of the formation of "tangles" of tangled strands of tau protein, which are the real cause of damage. Brain cells begin to die precisely in regions containing such aggregates of tau protein.
In brain tissue, the TREM2 protein is identified only on the surface of microglial immune cells. In experiments on mice, the authors demonstrated that in its absence, immune cells lose the ability to generate the energy they need to prevent the formation of amyloid plaques.
To study the effect of TREM2 on tau protein, they used genetically modified mice carrying a mutant form of human tau protein prone to the formation of toxic strands. They removed the TREM2 gene in some mice. As a result, toxic strands formed in all animals, while only a part of them had the TREM2 protein on microglial cells.
At the age of 9 months, the brain of mice with both tau-strands and TREM2 protein visually decreased in size, while the regions responsible for memory were particularly affected. At the same time, the damage was significantly less pronounced in mice without TREM2 protein.
To their surprise, the researchers found that the number of tau strands in the brains of the mice of the two groups did not differ much. Instead, the key difference was the response of immune cells to these strands. Microglia of animals with TREM2 protein actively released compounds that, under certain conditions, help in the fight against the disease, but in this case they mainly caused damage and death of surrounding neurons. The microglia of mice lacking the TREM2 protein were much less active, and the neurons were relatively intact.
Immune cells (red) they are more active in the brain tissue of mice with the TREM2 gene (left) than in the brain of animals without it (right).
For many years, doctors have tried to treat Alzheimer's disease by affecting amyloid plaques or tau strands, but none of the therapeutic approaches has proved effective. Four years ago, the identification of the TREM2 gene as the main risk factor for the development of the disease provided specialists with new perspectives in the fight against the disease.
The data obtained by the authors indicate that attempts to treat Alzheimer's disease by affecting the function of TREM2 and activation of microglia may be a much more difficult task than it seems at first glance.
It is quite possible that microglia activation should be applied at the beginning of the disease, when amyloid plaques are just beginning to be deposited in the brain tissue. And at later stages, when clinical symptoms are already manifested, it seems more appropriate to suppress the activity of microglia. However, before starting clinical trials, these ideas need to be tested in detail on animal models.
Article by Leyns C et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy published in the journal Proceedings of the National Academy of Sciences.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Washington University School of Medicine: Alzheimer's gene poses both risk — and benefits.