Scientists at Washington University School of Medicine in St. Louis have discovered a potential method to protect the brain from damage linked to tau protein buildup. By using an antibody to block immune cells known as T cells from entering the brain, researchers helped mice with Alzheimer’s-like changes retain roughly 40 percent more tissue in memory-related regions, even though the amounts of tau remained similar. The findings, published on September 28 in Neuron, suggest a treatment strategy for Alzheimer's tau research that targets the brain's immune response rather than the protein deposits themselves.
When The Immune Response Damages The Brain
Tauopathies are neurodegenerative diseases where tau protein accumulates in twisted clumps. While Alzheimer’s disease belongs to this group, it also involves another protein called amyloid. In primary tauopathies, tau builds up without amyloid deposits.
Currently, two Alzheimer’s drugs, lecanemab and donanemab, target the amyloid plaques that develop between brain cells early in the disease. While these drugs can slow cognitive decline, they have not been shown to prevent brain cell death and do not treat primary tauopathies.
David M. Holtzman, MD, the study’s senior author and a professor at WashU Medicine’s Department of Neurology, notes that there is currently no treatment for tauopathies that actually decreases neurodegeneration. He adds that showing a real decrease in brain cell death makes it worth pursuing this pathway to prevent the devastating consequences of these diseases.
Holtzman’s laboratory previously identified T cells as a possible contributor to this damage. A 2023 study in Nature showed that T cells entered the brains of mice with tau buildup, gathering in areas with the most tau and causing neurodegeneration. Another related study published earlier in September in Nature Neuroscience found that these cells receive their instructions in lymph nodes outside the brain.
Blocking the Route Into the Brain
To understand how activated T cells reach the brain, the researchers focused on CXCL10, a chemical signal they found at elevated levels in their mouse model and that other groups have linked to Alzheimer’s disease. Activated T cells detect CXCL10 through a surface receptor called CXCR3, providing a route the cells can follow.
The new study, which included co-senior author Jason Ulrich, PhD, and first author Joshua T. Emmerson, PhD, tested whether blocking this route could protect brain tissue. In mice with tau accumulation, removing either CXCL10 or the CXCR3 receptor prevented T cells from infiltrating the brain, even when researchers deliberately triggered inflammation.
Brain Protection Without Removing Tau
The team then tested an antibody designed to block CXCR3. Young mice with existing tau buildup, but without substantial brain cell loss, received injections every five days for three and a half months.
Following the treatment, mice given the antibody had about half as many T cells in their brains compared to untreated animals. They retained more tissue in memory-related regions, showed fewer signs of nerve cell damage, and performed better on a memory test. However, their tau tangles looked much the same, suggesting that reducing the immune response could limit damage even while the underlying protein deposits remain.
Notably, the antibody reached the brain’s boundary without entering the brain tissue itself. This raises the possibility of treating the damaging process from outside the brain, bypassing the need to deliver therapy across the blood-brain barrier.
A New Role for T Cell Therapies
The results remain an animal finding, and more research is needed before the approach can be tested in people to see if it safely protects the human brain. The study also leaves open whether the treatment would help after substantial neurodegeneration has already occurred.
Holtzman suggested that existing drugs targeting T cells, some of which are already used for multiple sclerosis and other autoimmune disorders, could be evaluated as possible Alzheimer’s treatments.
For this therapeutic approach, if it is safe, you wouldn’t have to design the drug to get into the brain - which is a big deal since most molecules don’t cross the blood-brain barrier well - and you don’t have to get rid of the tau to get this therapeutic effect.
David M. Holtzman, MD, WashU Medicine
This article was written by AI from reporting by scitechdaily.com.
