Researchers at Washington University School of Medicine in St. Louis have identified a strategy to curb neurodegeneration in tauopathies, such as Alzheimer’s disease, by blocking an immune response rather than targeting protein buildup directly. By using an antibody to inhibit the CXCR3 protein in mice, the team successfully reduced T cell infiltration into the brain, preserving memory-center tissue and improving cognitive performance without altering tau levels.
The Immune System as a Driver of Damage
Current Alzheimer’s treatments like lecanemab and donanemab focus on clearing amyloid plaques, yet these therapies have not been shown to keep brain cells from dying. Research published in Neuron on Sept. 28 suggests that much of the damage in tauopathies—diseases characterized by the accumulation of twisted tau protein—is caused by the immune system’s response to these proteins rather than the tau itself.
Previous work from the laboratory of David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor in WashU Medicine’s Department of Neurology, established that T cells flood the brain in areas where tau is most abundant. A 2023 study in Nature confirmed that these T cells actively contribute to neurodegeneration. Subsequent research published in Nature Neuroscience clarified that these T cells receive instructions from lymph nodes located outside the brain.
Tracing the Chemokine Trail
To understand how activated T cells enter the brain, researchers investigated chemical trails known as chemokines. The team identified that a chemokine called CXCL10 is elevated in mouse models of tauopathy. Activated T cells express a surface protein, CXCR3, which allows them to follow the CXCL10 trail into the brain.
In the study led by 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 lab, researchers demonstrated that mice lacking either the CXCL10 chemokine or the CXCR3 receptor did not experience T cell infiltration into the brain, even when inflammation was induced.
Preserving Tissue While Tau Persists
The researchers tested a potential therapy by injecting young mice—which had already developed tau buildup but lacked significant cell loss—with an antibody that blocks CXCR3. The treatment was administered every five days over a three-and-a-half-month period.
The results showed a reduction of T cells within the brains of the treated mice by about half compared to the control group. The treated animals also retained approximately 40% more tissue in the brain’s memory centers and performed better on a memory test. Notably, the levels of tau tangles remained the same between the treated and untreated mice.
Rethinking Therapeutic Targets
This research suggests that neurodegeneration may be managed even if the underlying protein pathology persists. The team discovered that the therapeutic antibody traveled to the brain’s border but did not need to penetrate the brain tissue itself to be effective.
“In tauopathies, including Alzheimer’s disease, there’s no treatment right now that actually decreases neurodegeneration,” Dr. Holtzman stated. “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.”
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