Mice kept more brain tissue and performed better on a memory test after researchers blocked an immune attack, without removing the tau tangles linked to Alzheimer’s.
Scientists at Washington University School of Medicine in St. Louis have identified a potential way to protect the brain from damage associated with tau buildup. In mice with Alzheimer’s-like changes, an antibody reduced the entry of immune cells called T cells into the brain. Treated animals retained roughly 40% more tissue in regions involved in memory than untreated mice, despite having similar amounts of tau.
The findings, published Sept. 28 in Neuron, point to a treatment strategy focused on the brain’s response to tau rather than the protein deposits themselves. Growing evidence suggests that this immune response contributes substantially to the cell death that gradually erodes memory and independence.
When The Immune Response Damages The Brain
Tauopathies are neurodegenerative diseases in which tau protein accumulates in twisted clumps. Alzheimer’s belongs to this group, but it also involves another protein, amyloid. In primary tauopathies, tau builds up without amyloid deposits.
Two Alzheimer’s drugs, lecanemab and donanemab, target amyloid plaques that develop between brain cells early in the disease. Amyloid disrupts cellular communication and promotes the formation of tau tangles inside neurons. Although these drugs can slow decline, they have not been shown to prevent brain cell death and do not treat primary tauopathies.
“In tauopathies, including Alzheimer’s disease, there’s no treatment right now that actually decreases neurodegeneration,” said David M. Holtzman, MD, the study’s senior author and the Barbara Burton and Reuben M. Morriss III Distinguished Professor in WashU Medicine’s Department of Neurology. “If we can show that we’re really decreasing brain cell death, it’s certainly worth trying to pursue that pathway to prevent the most devastating consequences of these diseases.”
Holtzman’s laboratory previously identified T cells as a possible contributor to that damage. Its 2023 study in Nature showed that T cells entered the brains of mice with tau buildup, gathered especially in areas containing the most tau, and caused neurodegeneration. A 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
Those earlier findings left a crucial part of the process unexplained: how activated T cells reached the brain. Immune cells navigate by following chemical signals called chemokines. The researchers focused on CXCL10, a signal they had found at elevated levels in their mouse model and that other groups had linked to Alzheimer’s disease.
Activated T cells detect CXCL10 through a receptor on their surface called CXCR3. Together, the signal and receptor provide a route the cells can follow. Blocking that route offered a way to test whether keeping T cells out could protect brain tissue.
The new study included co-senior author Jason Ulrich, PhD, a professor of neurology at WashU Medicine, and first author Joshua T. Emmerson, PhD, a postdoctoral researcher in Holtzman’s laboratory. In mice with tau accumulation, removing either CXCL10 or the CXCR3 receptor on T cells prevented the cells from infiltrating the brain, even when the researchers deliberately triggered inflammation.
Brain Protection Without Removing Tau
The team then tested an antibody that blocks CXCR3. Young mice with existing tau buildup, but without substantial brain cell loss, received injections every five days for three and a half months.
At the end of treatment, mice given the antibody had about half as many T cells in their brains as untreated animals. They also retained more tissue in memory-related regions, showed fewer signs of nerve cell damage, and performed better on a memory test.
Yet their tau tangles looked much the same. That combination suggests that, in these mice, reducing the immune response could limit damage even while the underlying protein deposits remained.
The antibody also reached the brain’s boundary without entering the brain tissue itself. This raises the possibility of treating a damaging process from outside the brain, avoiding the need to deliver the therapy across the blood-brain barrier.
The results remain an animal finding. More research is needed before the approach can be tested in people, including whether it can safely protect the human brain. The study also leaves open whether treatment would help after substantial neurodegeneration has already occurred.
A New Role for T Cell Therapies
Holtzman suggested that existing drugs targeting T cells could be evaluated as possible Alzheimer’s treatments. Some are already used for multiple sclerosis and other autoimmune disorders, in which the immune system attacks healthy tissue.
“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,” said Holtzman, who also directs WashU Medicine’s Hope Center for Neurological Disorders and Knight Alzheimer Disease Research Center.
“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.”
Reference: “Peripheral CXCR3 blockade mitigates T cell infiltration and neurodegeneration in a mouse model of tauopathy” by Joshua T. Emmerson, Hao Hu, Vivek Savani, Peter Lin, Mina Rohde, Prabal Sharma, Wade Self, Yongyi Li, Jonathan Nulman, Megan E. Bosch, Zhe Liu, Javier Remolina Serrano, Xin Bao, Carla M. Yuede, Mehdi Jorfi, Rudolph E. Tanzi, Jason D. Ulrich and David M. Holtzman, 28 September 2026, Neuron.
DOI: 10.1016/j.neuron.2026.08.030
This study was supported by a BrightFocus Postdoctoral Fellowship, National Institutes of Health/National Institute on Aging grants R01AG082328 and R01AG085374, the GHR Foundation, the Carol and Gene Ludwig Initiative in Neuroimmunology Research, a gift from Ronald Schaich, a gift from John Ludwig, a gift from Cindy and Evan Goldberg, and the Freedom Together Foundation.
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