Side effect of rapamycin
Mouse trial: rapamycin increases the number of beta-amyloid plaques
Researchers from the University of Texas Health Science Center in San Antonio (UT Health San Antonio) found in a mouse model of Alzheimer's disease that oral administration of rapamycin causes an increase in the number of beta-amyloid plaques. The accumulation of beta-amyloid in the body is considered one of the most important factors provoking Alzheimer's disease.
Rapamycin (sirolimus, rapamun) is a powerful immunosuppressant used to prevent rejection of transplanted organs, has a certain application in the treatment of oncological diseases and is of interest to scientists as a potential cure for a wide range of ailments, from vascular abnormalities to aging. However, researchers from UT Health noticed that after treatment with rapamycin, the level of Trem2 protein sharply decreases. This protein is associated with microglia, a type of cell that performs an important immune function in the brain and spinal cord.
"Trem2 is a receptor located on the surface of microglia and allows these cells to absorb and destroy beta-amyloid," explains senior author of the study Manzoor Bhat (Manzoor Bhat). "The loss of Trem2 in microglia impairs the vital function of amyloid degradation, which, in turn, causes the accumulation of beta-amyloid, generates amyloid plaques."
It is important to note that the study published on June 7 in the Journal of Neuroscience (Shi et al., Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease Model) is not limited to the disturbing discovery of the role of rapamycin in the accumulation of beta-amyloid — its authors also demonstrated a new way to increase the amount of Trem2 in microglia. When the lead author of the study and associate professor of the Department of Cellular and Integrative Physiology, Dr. Qian Shi, removed a gene called Tsc1 from the microglia, there was a noticeable increase in the level of Trem2 and a decrease in the number of beta-amyloid plaques.
Previous studies have shown that the loss of Tsc1 leads to activation of the mTOR signaling pathway (a target of rapamycin in mammals). Rapamycin, on the contrary, blocks this pathway.
"We expected that selective loss of Tsc1 only in microglia, and not in neurons or other cells, would have negative consequences, since mTOR inhibition by rapamycin has known therapeutic applications in some disease models," said Dr. Shi. "But the opposite happened."
Thus, according to Dr. Shi, suppression of Tsc1 exclusively in microglia to enhance the absorption of beta-amyloid may be a potential target of new drug therapies.
The experiments were carried out on a specific line of 5XFAD mice used as a model of Alzheimer's disease in humans. According to Dr. Bhat, this study is related to Alzheimer's disease associated with beta-amyloid, and does not apply to other pathologies associated with Alzheimer's disease.
The results of this study may give the medical world a reason to suspend testing of rapamycin on people at risk of developing Alzheimer's disease.
"Rapamycin may have advantages in terms of suppressing the immune system and as a tumor suppressor," says Dr. Bhat. — However, in a situation where it negatively affects the expression of Trem2 or other critical proteins, this can have a detrimental effect. We warn that the benefits of rapamycin in betaamyloid-associated Alzheimer's disease should be studied more carefully."
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