Researchers at Washington University School of Medicine in St. Louis have developed a potential antibody-based approach to reducing neurodegeneration in diseases known as tauopathies, including Alzheimer’s disease. Studying mice with Alzheimer’s-like tau protein accumulation in their brains, the team showed that injecting the animals with an antibody to a protein called CXCR3 over several months blocked the route used by T cells to get into the brain, reducing the number of those cells in the brain by about half.
The treated mice kept roughly 40% more tissue in memory centers of the brain and did better on a memory test compared with untreated mice—even though the levels of tau in their brains didn’t change. “In tauopathies, including Alzheimer’s disease, there’s no treatment right now that actually decreases neurodegeneration,” said David M. Holtzman, MD, 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 is senior author of the team’s published paper in Neuron, titled “Peripheral CXCR3 blockade mitigates T cell infiltration and neurodegeneration in a mouse model of tauopathy,” in which they concluded “Our study defines the CXCR3 axis as a critical target that, when blocked, mitigates CD4+ and CD8+ T cell infiltration and confers neuroprotection in a model of tau-mediated neurodegeneration in vivo without influencing levels of soluble or insoluble tau.”
There is no treatment available today to stop the death of brain cells in tauopathies—including Alzheimer’s disease—in which twisted clumps of a protein called tau accumulate in the brain. Cells near those clumps begin to die after tau accumulates, but growing evidence suggests that much of the damage doesn’t come from the protein directly. Instead, it’s the immune system’s response to tau that’s to blame for the damage that eventually robs people of their memory and independence.
The two existing Alzheimer’s drugs on the market—lecanemab and donanemab—target amyloid protein, which forms plaques between brain cells in the early stages of the disease, disrupts cell communication, triggers tau tangles to form inside neurons and eventually leads to cell death. These anti-amyloid medications can slow a person’s decline, but they haven’t been shown to keep brain cells from dying, and they don’t work against primary tauopathies—diseases marked by tau buildup in which amyloid never appears. Alzheimer’s is a secondary tauopathy in which both amyloid and tau proteins accumulate.
Earlier research led by the Holtzman lab raised the possibility that targeting T cells could be an alternative route to treating tauopathies, including Alzheimer’s. In a paper published in 2023 in Nature, Holtzman’s lab showed that in mice with tau buildup, T cells flood into the brain, especially in areas where tau is most abundant, and cause neurodegeneration. In a related paper published earlier this month in Nature Neuroscience, the team showed that those T cells get their instructions from lymph nodes outside the brain.
In their newly published paper the team noted, “Beyond the roles of reactive microglia and astrocytes, recent work has demonstrated an important role of T cells and adaptive immunity in tau-mediated neurodegeneration, as suggested in human brains with advanced tauopathy and demonstrated in transgenic models.”
How T cells got into the brain once activated remained unknown, however. “The signaling pathways driving brain T cell homing and infiltration in tauopathies remain unknown, and identifying and targeting mechanisms for the prevention of such entry may offer therapeutic potential,” the investigators added.
The cells are known to navigate by following chemical trails called chemokines, and Holtzman’s team had previously found that one chemokine—called CXCL10—was elevated in the tau-mouse model they were utilizing. Other groups had shown that CXCL10 was elevated in Alzheimer’s. Activated T cells carry a protein on their surface, CXCR3, that follows this particular trail. “We hypothesized that the CXCR3 axis is an important chemotactic gradient for brain-infiltrating T cells in tauopathy, thereby linking peripheral immune activation to tau-driven brain injury,” they stated.
For their latest reported study the researchers, including 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, examined the brains of mice with tau accumulation, as happens in Alzheimer’s disease. They found that in mice that lacked the CXCL10 chemokine, or the receptor protein CXCR3 on T cells that binds to CXCL10, T cells did not infiltrate the brain, even when researchers deliberately provoked inflammation to elicit an immune response.
The team then injected an antibody that blocked CXCR3 into young mice that had tau buildup in their brains but hadn’t yet had major brain cell loss. Treatment was administered every five days for three and a half months. The results showed that compared with the untreated mice, treated animals had about half as many T cells in their brains at the end of treatment. The treated animals also preserved more brain tissue and exhibited less evidence of nerve cell damage. “In a mouse model of tauopathy and neurodegeneration, chronic systemic anti-CXCR3 treatment markedly reduced parenchymal CD4+ and CD8+ T cell accumulation, attenuated neurodegeneration, and improved aspects of cognition,” they noted.
Yet tau tangles appeared the same in treated and untreated animals. “A key point of interest was the rescue from neurodegeneration but no overt changes to tau pathology,” the researchers added.
Tests by Holtzman’s team also revealed that the antibody traveled to the border of each animal’s brain but not into the brain tissue—an important finding indicating that neurodegeneration can be treated without having to get a therapy into the brain itself.
“Our findings implicate a critical role of CD4+ T cells in accelerating tau-mediated neurodegeneration and suggest that peripheral CXCR3 inhibition could be a therapeutic approach in tauopathies,” the investigators said.
While more research is needed before the approach could be tested in people, Holtzman noted that existing drugs that target T cells—such as some therapies used for multiple sclerosis and other autoimmune disorders that occur when the body’s immune system attacks its own healthy cells—could be evaluated as Alzheimer’s therapies, opening a new therapeutic avenue for the disease.
“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’s Hope Center for Neurological Disorders and the Knight Alzheimer Disease Research Center at WashU Medicine. “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.”