Scientists have reported on a new way to protect the brain in Alzheimer's disease
It was possible to protect the brain from Alzheimer's-related damage without removing abnormal protein accumulations. In an experiment on mice, scientists blocked the path of immune cells involved in the destruction of nervous tissue. The animals performed better at memory testing, and about 40% more tissue was preserved in the areas of the brain responsible for it than in the control group. Why our own defense system can damage the brain and how scientists are trying to stop this process — in the Izvestia article.
Why are scientists looking for the cause of damage beyond protein clusters?
In Alzheimer's disease, two characteristic forms of pathological protein deposits accumulate in the brain. Beta-amyloid forms plaques between nerve cells, and tau protein forms tangles inside them. These changes are associated with impaired neuron function, memory impairment, and death of nervous tissue.
The study was conducted by a team from Washington University School of Medicine in St. Louis. The first author was Joshua Emmerson, the senior authors are Jason Ulrich and David Holtzman.
The scientists worked with a mouse model of tauopathy, a disease associated with abnormal accumulation of tau. It reproduces individual processes characteristic of Alzheimer's disease and related neurodegenerative conditions. Such an experiment allows us to test the mechanisms of brain damage, although it does not reproduce the human disease in all its complexity.
How protective cells can support Inflammation
The team had an interest in T-lymphocytes long before the current experiment. The researchers showed the interaction of these cells with microglia, the brain's own immune cells.
In experiments on mice, microglia isolated substances that attract T-lymphocytes from the blood and promoted their activation. These, in turn, released signals that increased the inflammatory activity of microglia. There was a mutually supportive reaction associated with damage to neurons.
When scientists removed one of the links in this chain, the severity of the damage decreased. Especially many T-lymphocytes were found in the brain regions of mice with the most pronounced neurodegeneration. They were also found near clusters of tau and damaged tissue in brain samples from people who died with Alzheimer's disease. These observations raised the following question for the researchers: how do immune cells receive a signal to go to the brain and whether it is possible to interrupt their movement.
How the route to the brain was blocked
Immune cells move through the body, guided by chemical signals. Among such signaling substances are chemokines: they help direct cells to where the immune response develops.
In the new work, the researchers focused on the chemokine CXCL10. Previously, its elevated level was found in the mouse model used, and other scientific groups reported an increase in this indicator in people with Alzheimer's disease.
The CXCR3 receptor, which recognizes CXCL10, is located on the surface of activated T-lymphocytes. Conventionally, this pair can be compared to a pointer and a receiver: one sets the direction, the other allows the cell to follow the signal.
To test the significance of this mechanism, the scientists studied mice that lacked either the signaling protein itself or the corresponding receptor on T cells. Under these conditions, the penetration of T-lymphocytes into the brain tissue did not occur even after artificially triggering an inflammatory reaction.
The team then tested an approach closer to the future treatment, blocking CXCR3 with an antibody. Instead of genetically eliminating a link in the system, the researchers prevented it from working with a drug.
What has changed after three and a half months of treatment
For the experiment, we selected young mice that had already accumulated pathological tau, but had not yet experienced significant loss of nerve cells. The antibody was administered once every five days for three and a half months.
By the end of the study, the number of T-lymphocytes in the brains of the treated animals was about half that of the comparison group. They showed less pronounced signs of neuron damage and better preservation of brain tissue.
Approximately 40% more tissue was preserved in the areas involved in memory. This is a comparison with the control group: the indicator does not mean that the treatment restored 40% of the already dead cells. The results of the behavioral test were also better. The authors evaluated the recognition of a new object, which is one of the ways to study memory in laboratory animals. Thus, the effect manifested itself both in the condition of the tissues and in the performance of the task.
At the same time, the amount of pathological tau has not changed significantly. It is the combination of these results that makes the work significant: in this model, it was possible to reduce brain damage without a noticeable reduction in protein deposits. This does not mean that tau is harmless. The experiment shows that the severity of the effects of its accumulation can be influenced through the associated immune mechanism.
How does the approach differ from amyloid removal?
One of the directions of modern therapy of Alzheimer's disease is associated with antibodies against amyloid. These include lecanemab and donanemab, which act on amyloid deposits.
According to the US Food and Drug Administration (FDA), donanemab slowed the deterioration of cognitive functions and daily abilities in patients in the early symptomatic stages of the disease. The drug was studied in people with confirmed amyloid pathology and mild cognitive impairment or mild dementia.
The new work explores another target, the movement of T—lymphocytes involved in nerve tissue damage. This area is also potentially interesting for primary tauopathies, in which pathological tau accumulates without the amyloid plaques characteristic of Alzheimer's disease.
However, it is not yet possible to compare the effectiveness of these approaches: antiamyloid drugs have been tested in humans, and the blocking of CXCR3 in the described work was tested in mice.
What needs to be checked before human trials
The most important issue is the safety of long—term effects on the immune system. T-lymphocytes perform the necessary protective functions, so future therapy should reduce the pathological reaction without unacceptable consequences for the body.
It remains to be seen at what stage the intervention can help. In the experiment, treatment was started after the appearance of tau deposits, but before significant loss of neurons. The work does not show whether it is possible to restore already destroyed nervous tissue in this way or to achieve a comparable effect in a far-reaching disease.
Holtzman admits that some drugs that affect T cells and are used for multiple sclerosis and other autoimmune diseases may become a starting point for further research. However, their possible benefit in tauopathies requires a separate check.
The main achievement of the experiment is the confirmation that in a mouse model it is possible to interfere with a specific immune mechanism and preserve more nervous tissue, even when the pathological protein remains. Now, scientists will have to establish how important this mechanism is for human disease and whether it can be safely used for treatment.
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