Scientists talked about the role of lymph nodes in brain damage
The immune mechanism that can enhance brain damage in Alzheimer's disease and other diseases associated with the accumulation of tau protein may be triggered outside the central nervous system. This conclusion was reached by scientists at Washington University School of Medicine in St. Louis during experiments on mice. This is stated on September 3 in a study published in the journal Nature Neuroscience.
Alzheimer's disease and some forms of frontotemporal dementia are accompanied by the formation of pathological accumulations of tau protein in brain cells. At the same time, the content of immune cells, primarily cytotoxic CD8+ T lymphocytes, increases in the affected tissue. Previously, researchers had found that eliminating these cells from the brains of mice weakened neurodegeneration, but it remained unknown exactly where the T-lymphocytes received the signal to attack.
The scientists used genetically modified mice with the accumulation of pathological tau protein and the human variant of the APOE4 gene, which increases the risk of Alzheimer's disease. In some animals, the researchers genetically eliminated cDC1 cells, while in another group they disrupted the mechanism that allows these cells to present antigens to T-lymphocytes.
In both cases, the number of CD8+ T cells in the brain decreased significantly. The animals also showed less inflammation, the hippocampus and areas of the cortex were better preserved, and the layer of neurons in the dentate gyrus was thicker than in the mice from the control group. In addition, the animals performed better at building nests — this test is used to assess behavioral disorders in neurodegeneration.
At the same time, the elimination of cDC1 had no pronounced effect on the accumulation and phosphorylation of tau protein. According to the authors, this indicates that the discovered immune mechanism probably acts after the formation of tau pathology and increases the damage to the nervous tissue caused by it.
Additional experiments showed that antigens from the brain were predominantly presented to immune cells in the deep cervical lymph nodes. It is assumed that substances released from damaged neurons enter there along with cerebrospinal fluid through the lymphatic system of the meninges. Dendritic cells recognize these substances, activate CD8+ T lymphocytes, after which they enter the brain and support the inflammatory response.
It is not yet known which natural antigen triggers this process. Scientists have found fragments of tau protein, light chain neurofilament, and other nervous tissue proteins among the molecules represented by the immune system, but none of them has yet been recognized as a direct triggering factor.
A study of tissue samples from people with primary tauopathies also showed an increased content of CD8+ T cells in the gray and white matter of the brain. However, the involvement of cDC1 and the proposed sequence of immune reactions directly in humans have not yet been proven.
Senior author of the study, David Holtzman, professor of neurology at the University of Washington, noted that discovering a mechanism beyond the brain can simplify the development of therapy. According to the scientist, methods of controlling T-cell activity have already been studied and are used in other diseases, but their capabilities in neurodegenerative disorders remain virtually unexplored.
However, the results cannot yet be considered as a ready-made treatment for Alzheimer's disease. The main experiments were conducted on mice, and cDC1 cells or their ability to represent antigens were genetically disabled from an early stage of life. Now the scientists intend to find out whether the intervention will have a comparable effect in middle age, when the accumulation of tau protein is already beginning, and also to determine the signal that directs activated T cells to the brain.
On July 24, Science Daily reported the discovery of a mechanism to protect the brain from Alzheimer's disease. According to the publication, the rare longevity gene APOE2 is able to fight the disease by helping brain cells protect and repair their DNA. The scientists also found that adding the APOE2 protein to cells with the dangerous APOE4 variant reduces the activity of DNA damage signals.
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