T cells’ role in Alzheimer’s suggests a new treatment strategy

Drug development possibilities for brain diseases linked to tau protein.


One of the distinguishing features of Alzheimer’s disease is the extracellular deposition of amyloid-as neuritic plaques and the intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles. The mechanisms of tau-mediated neurodegeneration are still unknown. The regional progression of brain atrophy in Alzheimer’s disease strongly correlates with tau accumulation but not amyloid deposition.

Almost two dozen experimental immune-targeting medicines are being tested in clinical trials for Alzheimer’s disease, reflecting the growing knowledge that immunological processes are crucial in causing brain damage that leads to confusion, memory loss, and other severe symptoms.

Several Alzheimer’s medications under development target microglia, the brain’s resident immune cells that can harm brain tissue if triggered at the wrong time or in the wrong way. According to a recent study from Washington University School of Medicine in St. Louis, microglia interact with another type of immune cell, T cells, to trigger neurodegeneration.

The researchers discovered that microglia recruit potent cell-killing T cells into the brain of mice with Alzheimer’s-like damage in their brains due to the protein tau and that most of the neurodegeneration could be avoided by blocking the T cells’ entry or activation.

Xiaoying Chen, Ph.D., a neurology instructor, examined immune cells in the brains of mice genetically engineered to reflect many elements of Alzheimer’s disease in humans. She discovered that T cells were most abundant in areas of the brain with the most degeneration and the largest concentration of microglia and that the two types of immune cells collaborate to create an inflammatory environment conducive to neuronal damage.

Removing either microglia or T cells disrupted the harmful link between the two, resulting in significantly less brain damage. Also, when tau mice were given an antibody to decrease their T cells, they had fewer inflammatory microglia in their brains, less neurodegeneration and atrophy, and a better capacity to perform activities like building a tower.

Alzheimer’s disease progresses in two stages. Plaques of the protein amyloid beta begin to form first. Plaques can accumulate for decades without affecting brain health. .however, tau eventually accumulates, signifying the second phase’s start. The condition quickly worsens from there: the brain shrinks, nerve cells die, neurodegeneration spreads, and people have difficulty thinking and remembering.

Senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology, said, “This could change how we think about developing treatments for Alzheimer’s and related conditions. Before this study, we knew that T cells were increased in the brains of people with Alzheimer’s disease and other tauopathies. However, we didn’t know for sure that they caused neurodegeneration.”

“These findings open up exciting new therapeutic approaches. Some widely used drugs target T cells. Fingolomid, for example, is commonly used to treat multiple sclerosis, an autoimmune brain and spinal cord disease. Some drugs that act on T cells could likely be moved into clinical trials for Alzheimer’s disease and other tauopathies if these drugs are protective in animal models.”

Holtzman said, “What got me very excited was that if you prevent T cells from getting into the brain, it blocks the majority of the neurodegeneration. Scientists have put much effort into finding therapies that prevent neurodegeneration by affecting tau or microglia. As a community, we haven’t considered what we can do to T cells to prevent neurodegeneration. This highlights a new area to understand better and therapeutically explore.”

Journal Reference:

  1. Chen, X., Firulyova, Manis, et al. Microglia-mediated T-cell infiltration drives neurodegeneration in tauopathy. Nature. DOI: 10.1038/s41586-023-05788-0
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