Blocking Immune Cells Protects Memory and Brain Tissue in Alzheimer’s Mice

Immune Cells Drive Brain Damage in Tauopathy

Recent studies at Washington University School of Medicine in St. Louis have revealed a significant advance in neurology. Researchers demonstrated that preventing immune cells from entering the brain can preserve both memory function and brain structure in mice with a pathology similar to Alzheimer’s, characterized by the presence of tau protein. This therapeutic approach reduced the number of infiltrating T cells by about half while ensuring an additional 40% preservation of tissue in regions essential for memory. A crucial aspect of this discovery is that the positive effects were achieved without needing to cross the blood-brain barrier and without reducing tau levels in the body.

Inflammation, Not Tau Alone, Causes Neuron Loss

In neurodegenerative conditions broadly termed tauopathies, with Alzheimer’s as the primary example, tangled tau protein knots form inside neurons, followed by extensive cell death in vital cognitive centers. However, recent scientific evidence suggests that tau aggregates are not necessarily the direct cause of brain cell death. Instead, the destructive inflammatory reaction of the immune system, triggered by tau presence, is responsible for most observed damage. Current therapies, such as lecanemab and donanemab, target amyloid plaques, which appear in early disease stages and promote later tau accumulation. Although these drugs may slightly slow cognitive decline, they do not halt ongoing cell loss and offer no significant clinical benefit in primary tauopathies, where tau accumulates without amyloid.

Blocking CXCR3 Receptor Prevents T Cell Entry

A new study conducted by the research team offers an innovative therapeutic strategy, published in the journal Neuron. The group showed that blocking a specific chemokine portal retains destructive immune cells outside the central nervous system, significantly reducing neurodegeneration. David M. Holtzman, distinguished professor in the Department of Neurology at WashU Medicine and senior author of the study, emphasized that currently, no treatment effectively reduces neurodegeneration in tauopathies, including Alzheimer’s disease. He noted that demonstrating a real reduction in brain cell death justifies efforts to pursue this path to prevent the most severe consequences of these conditions.

Chemokine CXCL10 Guides T Cells to the Brain

Earlier work from Holtzman’s lab had shown that when tau accumulates in the brain, activated T cells from external lymph nodes flood affected regions, triggering cell death. The exact mechanism by which these guided cells cross the cerebral boundary remained unclear until now. It was known that T cells navigate along chemical gradients called chemokines. Researchers observed that a particular chemokine, CXCL10, increases sharply both in tau model mice and in human Alzheimer’s patients. Activated T cells possess a surface receptor named CXCR3, which directly follows the trail left by CXCL10 toward neural tissue. In experimental mice lacking both CXCL10 and the CXCR3 receptor, T cells failed to enter the brain, even when acute inflammation was artificially induced.

Anti-CXCR3 Antibody Therapy Preserves Brain Tissue

Based on this understanding, the team administered an antibody targeting CXCR3 to young mice with tau accumulation every five days for three and a half months. The results were striking: the number of infiltrating T cells inside the brain decreased by approximately 50%. Treated animals preserved about 40% more brain tissue in memory-essential circuits. Cognitive performance on memory tests was significantly superior compared to the untreated control group. Protective effects were evident even though the total burden of tau tangles remained completely identical between the two groups.

Challenge of Crossing the Blood-Brain Barrier

One of the major challenges in neurological pharmacology is designing drugs capable of crossing the blood-brain barrier, an extremely tight structure.