A study by researchers at Washington University School of Medicine in St. Louis identifies a method to disrupt immune system activity linked to brain cell loss in tauopathies—conditions like Alzheimer’s where abnormal tau protein accumulates. Unlike current treatments, which fail to halt neurodegeneration, the research suggests targeting immune responses rather than the tau itself could mitigate damage in these progressive diseases.
As tau protein forms clumps in the brain, cells nearby start to die. However, recent research indicates that the protein itself isn’t the main cause of the harm. Instead, the immune system’s reaction to tau is responsible for the damage that leads to memory loss and loss of independence.
Blocking T Cells’ Path into the Brain
Researchers worked with mice exhibiting Alzheimer’s-like tau buildup in their brains. By injecting these mice with an antibody targeting the CXCR3 protein over several months, they blocked the pathway that T cells use to enter the brain. This intervention reduced the number of these immune cells in the brain by approximately half.
The treated mice retained about 40% more tissue in brain regions associated with memory and performed better on memory tests than untreated mice, despite no change in their brain tau levels. The research is documented in the journal Neuron.
According to David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor in WashU Medicine’s Department of Neurology and the study’s senior author, “In tauopathies, including Alzheimer’s disease, there’s no treatment right now that actually decreases neurodegeneration.”
Lecanemab and donanemab are the two Alzheimer’s medications currently available. They target amyloid, a protein that creates plaques between brain cells during the disease’s early stages. While these anti-amyloid drugs can slow a person’s decline, they do not prevent brain cell death and are ineffective against primary tauopathies.
Previous studies from the Holtzman lab suggested that targeting T cells might offer an alternative route to treating tauopathies, including Alzheimer’s. In a 2023 paper published in Nature, Holtzman’s team demonstrated that in mice with tau accumulation, T cells migrate into the brain, particularly in areas with the highest tau concentration, causing neurodegeneration.
In the new work, researchers examined the brains of mice with tau accumulation as happens in Alzheimer’s disease. They found that in mice lacking the CXCL10 chemokine or the CXCR3 receptor protein on T cells, T cells did not infiltrate the brain, even when inflammation was provoked.
The team then administered an antibody blocking CXCR3 to young mice with tau buildup but no significant brain cell loss, giving the treatment every five days for three and a half months. Treated mice had roughly half as many T cells in their brains compared to untreated mice at the end of treatment.
Testing revealed that the antibody reached the brain’s border but not its tissue, suggesting neurodegeneration can be addressed without direct brain therapy. The CXCR3 blockade reduced T cell infiltration and neurodegeneration in the tauopathy mouse model, as detailed in the study Peripheral CXCR3 blockade mitigates T cell infiltration and neurodegeneration in a mouse model of tauopathy.
While more research is needed before testing in humans, existing T cell-targeting drugs, such as those for multiple sclerosis, could be evaluated for Alzheimer’s. Holtzman noted, “Tauopathies aren’t thought of as autoimmune disorders, so they haven’t been treated the same way, but this study shows for the first time in an animal model that these diseases respond to a specific T-cell therapy.”
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