Science3 publishers2 min readPublished
Antibody that keeps T cells out of the brain preserved memory tissue in tauopathy mice
Washington University researchers report that a CXCR3-blocking antibody halved brain T cells and spared 40% more memory-region tissue in tauopathy mice. Tau levels never fell, evidence the immune reaction to tau does much of the killing.
The Scientist · Science desk
What happened
- Treated mice performed significantly better on a memory test than untreated animals that carried the same load of tau tangles.
- The antibody accumulated only at the structural borders of the brain and did not enter the deep tissue, so it acted from the periphery.
- A related study the same group published in Nature Neuroscience on September 3 traced the invading T cells back to activation in lymph nodes outside the brain.
- The two approved Alzheimer's drugs, lecanemab and donanemab, target amyloid and have not been shown to keep brain cells from dying.
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Why it matters
- capability A therapy built on this route would not have to be engineered to cross the blood-brain barrier, the obstacle that stops most nervous-system drugs before they reach the tissue.
- decision Because drugs that manipulate T cells are already approved for other diseases, those existing agents become candidates to test against tauopathy rather than compounds built from scratch.
- constraint The tau protein was left untouched, so the approach blunts the immune damage without removing what provokes it; whether the residual tau harms the brain over a longer course is untested.
- exposure For primary tauopathies, where amyloid never appears and the approved anti-amyloid drugs do nothing, an immune-entry route opens a strategy those patients did not have.
T cells find their way by following chemical trails called chemokines. Holtzman's group had found that one of those trails, a chemokine called CXCL10, runs high both in the tau mouse model they used and in people with Alzheimer's disease [1]. Activated T cells carry a surface receptor, CXCR3, that reads the CXCL10 signal and follows it into brain tissue [2]. When the team bred mice without either CXCL10 or CXCR3, the cells could not get into the brain even after the researchers set off inflammation on purpose [3]. The antibody blocks that same receptor from the blood side.
The antibody built up at the structural borders of the brain and did not reach the deep tissue [4]. "One of the issues in developing treatments for neurological diseases is that you need to engineer your treatment so that it gets into the brain and past the blood-brain barrier, but we might not actually need to get the drugs into the central nervous system to mitigate neurodegeneration," Holtzman said [5].
The tissue survived without any drop in tau. Levels of both soluble and insoluble tau were the same in treated and untreated animals [6]. In the paper, published in the journal Neuron [20], the authors wrote that the CXCR3 axis is "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" [7].
The study does not settle whether any of this carries to people. The animals were young and carried Alzheimer's-like tau buildup, and the antibody went in every five days for three and a half months [8]. The reports describe the memory result only as significantly better than untreated controls; they do not put a number on it [9]. And because the protein itself was left in place, the work shows that blocking immune entry protects tissue, not that the tau is harmless once the T cells are held back.
"In tauopathies, including Alzheimer's disease, there's no treatment right now that actually decreases neurodegeneration," Holtzman said. "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." [18]
What to watch
- Whether the antibody protects older mice or animals that already carry advanced tau tangles, not only young mice dosed early.
- Whether an existing, approved T-cell drug can reproduce the effect and move into human trials for tauopathy.
- Whether human tauopathy patients show the same CXCL10-to-CXCR3 T-cell entry route seen in the mouse brains.