In the early stages of Alzheimer's disease, before symptoms begin to show, amyloid proteins build up between brain cells. These amyloid bundles, or plaques, trigger the accumulation of sticky clumps of a protein called tau in cells that lead to cell death.

This neurodegeneration or cell death leads to memory loss and, eventually, the inability of people with Alzheimer's disease to live independently.

It's not the clumps of tau proteins that cause cell death, however. Cells die when T-cells enter the brain as part of an immune response to the damage caused by tau buildup. T-cells are guided to damaged tissue by proteins called chemokines, chemical messengers that control immune response and inflammation. This process has not really been studied in connection to neurodegenerative diseases like Alzheimer's disease.

Cells die when T-cells enter the brain as part of an immune response to the damage caused by tau buildup.

A team at Washington University in St. Louis decided to try to find out which chemokines and receptors on the surface of T-cells guide T-cells into the brain. The researchers, led by David Holtzman, used a mouse model with tau protein buildup in the brain characteristic of Alzheimer's disease. They already knew that the brains of these mice had high levels of a chemokine called CXCL10 and that other researchers had found CXCL10 levels were elevated in Alzheimer's disease.

A receptor on the surface of T-cells, called CXCR3, binds to the CXCL10 chemokine. When the researchers injected mice every five days over several months with an antibody that blocked CXCR3, this blockade prevented T-cells from entering the brain. The number of T-cells in the brain was reduced by about half.

Most of the T-cells that could not get into the brain were a specific subtype called Th1-like CD4+ CXCR3+ T-cells. Holtzman, co-senior author of the study, found this surprising, “That subtype of T-cell must be involved in brain injury,” he told TheDoctor. He had thought blocking the CXCR3 receptor might prevent all types of T-cells from entering the brain.

Antibody-treated mice also had about 40 percent more tissue left in the memory centers of their brain and less brain damage compared to the untreated mice. They did better on a memory test, even though their brains still had the same amount of tau protein.

Antibody-treated mice had about 40 percent more tissue left in the memory centers of their brain and less brain damage. They did better on a memory test even with the same amount of tau protein in their brain.

These findings suggest that blocking CXCR3 may be a way to treat neurodegenerative diseases. Two medications on the market, lecanemab (sold as Leqembi) and donanemab (sold as Kisunla), target amyloid plaques. Treatments that prevent subsequent tau buildup and the death of brain cells are currently unavailable.

The researchers found that the CXCR3 antibody did not cross the blood-brain barrier into the brains of the mice. This finding is important, they explained, because it suggests that neurodegeneration can be treated without having to insert treatment into the brain itself.

“This is kind of a big deal because most molecules don't cross the blood-brain barrier well,” Holtzman, the Barbara Burton and Reuben M. Morriss III Distinguished Professor in the department of neurology at Washington University School of Medicine, said. And the treatment would not have to eliminate tau buildup to have a beneficial effect.

Though exciting and promising, this is preliminary work. The antibody the researchers used is specific for the rodent version of CXCR3, so, as Holtzman explained, they will need to make an antibody to the human version of CXCR3 and show it works in animals. If it does, the next step will be human trials.

The study is published in Neuron.