The specialized cells of the immune system that must protect the body from infections and cancers show their dark side in Alzheimer’s, when they attack the brain itself and accelerate neurodegeneration. This is demonstrated by research from Washington University in St. Louis (USA) that is being presented today in the journal Nature and which suggests that the progression of the disease could be slowed down with immunotherapy treatments.
The novelty of the work focuses on the tau protein, which, together with beta-amyloid, is one of the two main proteins altered in Alzheimer’s. Beta-amyloid, against which drugs have already begun to be developed, accumulates from the onset of the disease outside the neurons. Tau, for which there are still no treatments, accumulates inside neurons in a more advanced stage of Alzheimer’s, when symptoms worsen.
Researchers at Washington University have shown in experiments with mice that when there is an abnormal accumulation of tau protein in the brain, the activity of cytotoxic T lymphocytes, a type of immune cell that has the ability to destroy other cells, increases. In contrast, the accumulation of beta-amyloid protein does not cause any changes in T lymphocytes.
They have also discovered how lymphocytes cause damage in the brain. Specifically, the microglia (which are immune cells resident in the brain itself) tell the lymphocytes (which come from outside as riot squads) which cells to attack. From then on, the lymphocytes just do their job: they attack the cells on command, causing progressive atrophy of the brain.
Finally, the researchers have shown that neurodegeneration in mice can be halted with an immunosuppressive treatment that blocks T lymphocytes. Three different behavioral tests have confirmed that cognitive decline in mice is not only halted but partly reversed.
One of the tests has evaluated the short-term memory to navigate a maze, another the memory related to an emotional stimulus and the third the nest building behaviour. In all three cases, “a significant improvement” has been observed with respect to the behavior of the mice before receiving the immunosuppressive treatment, the researchers write in Nature.
“If T cells are prevented from accessing the brain, most neurodegeneration is prevented,” says David Holtzman, director of the research, in a statement from Washington University. “This could change the way we think about developing therapies for Alzheimer’s.”
Until now, pharmaceutical companies have focused on developing therapies against the beta-amyloid protein, but the results so far have been below expectations – although lecanemab has already been approved in the US and is pending approval in Europe later. to prove that it slows down the progression of the disease in its initial phases. There are also ongoing studies to treat Alzheimer’s by acting on microglia, although still without results. Acting on T lymphocytes offers a new treatment option that would not act at the onset of the disease but could prevent or delay its progression to dementia.
There are already approved drugs that act on T lymphocytes, Holtzman points out. According to his reasoning, since Alzheimer’s has an autoimmune component, drugs developed for other autoimmune diseases could be useful for people with Alzheimer’s. Holtzman cites the example of fingolomid, already approved for multiple sclerosis, another autoimmune disease that affects the nervous system. “It is probable that some drugs that act on T lymphocytes could enter clinical trials for Alzheimer’s,” says the researcher.
Unlike drugs against beta-amyloid, which take a long time to find out if they are effective because they are tested in the early stages of a slow-onset disease, treatments against tau protein could offer clear results in a way faster. This would allow for shorter clinical trials and, if the results are positive, shorten the time it takes for drugs to reach patients.
“The research provides new evidence on the role of the immune response in Alzheimer’s disease and demonstrates the involvement of T lymphocytes”, highlights Alberto Lleó, director of the neurology service at the Sant Pau hospital in Barcelona. Lleó points out that “Holtzman’s group has a solid track record in this area”, but warns that “studies in animal models of Alzheimer’s should always be interpreted with caution”.
According to the specialist from Sant Pau, who is participating in clinical trials of treatments for Alzheimer’s, “a good understanding of the relationship between the two immune responses [that of microglia and that of T lymphocytes] will be important to find drugs that complement anti-inflammatory treatments.” -amyloid that will probably be approved in the next few years”.