nasal treatment appears to be effective regardless of the level of amyloid plaques

Monoclonal antibody nasal drops improved cognitive function in mouse models of Alzheimer’s disease regardless of amyloid plaque levels. The drug, originally developed to treat multiple sclerosis (MS), reduces inflammation in the brain. Its mode of action offers hope of a cure for people with advanced disease.

In recent years, the famous “amyloid cascade” theory of Alzheimer’s disease has been called into question. From now on, the abnormal accumulation of amyloid plaques in neurons is no longer considered the main cause of the disease, but only one of its characteristics. One reason leading to the debate is the lack of effectiveness of treatments targeting these proteins. These treatments constitute the vast majority of therapeutic strategies against the pathology and are used almost exclusively in the early stage.

Various hypotheses have been put forward to explain the pathogenesis of the disease, such as the involvement of the intestinal microbiota or the accumulation of iron in the white matter. However, the viability of these theories has not yet been truly tested. Because neuroinflammation is a major component of Alzheimer’s disease, many therapeutic studies are aimed at reducing it in hopes of mitigating patients’ cognitive decline.

Intervention at the level of neuroinflammation

Neuroinflammation is characteristic of most neurodegenerative diseases, such as multiple sclerosis and Alzheimer’s disease. In the case of the latter, activation of microglia and astrocytes at the level of amyloid plaques suggests significant involvement of inflammatory pathways. Most genetic risk factors are associated with proteins expressed by immune cells. Previous studies have shown that following neuroinflammation, microglia transition from homeostasis to a neurodegenerative phenotype.

On the other hand, adaptive (or regulatory) immune cells play an important role in promoting or suppressing neuroinflammation. Among these cells are regulatory T cells (Treg), which modulate the immune response and maintain immunological tolerance. In addition, these cells eliminate excessive and potentially harmful immune responses. Experiments showed that transferring Tregs into mouse models of Alzheimer’s disease improved cognitive function, while reducing them worsened cognitive deficits. This also applies to other neuroinflammatory diseases such as multiple sclerosis.

Based on these results, researchers at Brigham and Women’s Hospital at Harvard University came up with the idea of ​​reducing neuroinflammation caused by Alzheimer’s disease using anti-CD3 monoclonal antibodies. CD3 is a protein complex responsible for enhancing the immune response upon expression of Tregs. ” There is clear evidence of Treg dysfunction in Alzheimer’s disease, and improving Treg function is expected to be beneficial for its treatment. “,” they point out in their new study published in the journal
PNAS.

Improvement in symptoms has been observed in previous studies using anti-CD3 antibodies in mouse models of multiple sclerosis, diabetes, lupus and arthritis. In models of multiple sclerosis, anti-CD3 nasal drops have shown particular promise in reducing inflammation caused by microglial and astrocyte migration. Given the involvement of microhyal hyperactivation in Alzheimer’s disease, the drops were tested in this disease as part of a new study. Note that these antibodies are also used as immunosuppressants against transplant rejection.

Action independent of the number of amyloid plaques

In the new trials, anti-human CD3 nasal drops were tested on groups of male and female mice (1 to 6 months old) genetically modified to develop Alzheimer’s disease. Treatment was carried out 3 times a week for 5 months. After an acclimatization period of approximately 3–4 weeks, behavioral tests (assessing short-term and long-term memory and spatial learning) were performed throughout the day.

After evaluation, it was found that the treated mice showed better behavioral results, indicating an overall improvement in cognitive function. Analyzing the brain, the researchers found that microglial activation markedly decreased, while peripheral Treg cells (which reduce microglial migration) increased. ”
We provide evidence that intranasal anti-CD3 therapy can suppress microglial activation and increase T cell numbers in a mouse model of Alzheimer’s disease. “said study author Howard Weiner of the Department of Neurology at Brigham and Women’s Hospital in a statement.

Interestingly, the drug had no effect on the level of amyloid plaques. What’s even more surprising is that short-term memory improved only in female mice. Changes in gene expression patterns in the hippocampus, cerebral cortex, and microglia were also observed. These changes varied by gender and could explain the differences observed in short-term memory tests.

Due to its action independent of amyloid protein levels, the antibody could benefit people with advanced disease, which could be a major advantage over currently available treatments. ”
[L’anticorps] represents a unique approach to the treatment of advanced Alzheimer’s disease and may also be used in other inflammatory diseases. “,” says Weiner. It can be used either as a replacement or as an adjunct to other treatments that target the amyloid protein. As a next step before moving into clinical trials, the research team plans to expand the experiments to animal models, combining anti-CD3 with existing anti-amyloid treatments.

Source: PNAS