Around the world, approximately 33 to 38.5 million people have Alzheimer’s disease, a common type of dementia. Alzheimer’s causes people to struggle with concentration and thought, which can then cause them to forget things such as basic tasks and the names of people and places, as well as cause a shift in personality and behavior.
Oftentimes, Alzheimer’s is caused by a protein called tau, which is meant to assist neurons in maintaining the cell’s shape, assist the movement of nutrients and signals, and convert short-term memories into long-term memories. But tauopathies, the neurodegenerative disease group Alzheimer’s belongs to, causes tau to grow uncontrollably in the brain. What differentiates Alzheimer’s from other tauopathies are clumps known as amyloid plaques, which cause brain cells around these clumps to die.
So far, there has been no known cure for Alzheimer’s, only treatments that target removing amyloids, as well as two medications named lecanemab and donanemab. But a new study suggests that researchers may have gotten the approach to stop Alzheimer’s all wrong.
Recent evidence suggests that Alzheimer’s damage to the brain is caused not by tau itself, but rather the immune system’s response to it. Scientists at Washington University School of Medicine in St. Louis, led by the Holtzman lab found that T cells, a type of white blood cells that helps fight germs in the immune system, bring abnormal amounts of tau into the brain. This was found in a study involving young mice with tauopathies developed early enough without substantial brain cell loss.
Researchers focused on chemokine CXCL10 and chemokine receptor CXCR3, where chemokines are proteins that guide the movement of white blood cells throughout the body and chemokine receptors are the surface the cells are guided on. They observed that CXCL10 was found in high levels in the mice and other groups linked to Alzheimer’s disease, in which T cells would follow the route activated by CXCL10 on the surface of CXCR3.
Researchers ran multiple tests with the proteins, the first being the removal of either CXCL10 or CXCR3 receptors from the mice’s brain. This resulted in the T cells being unable to infiltrate the brain, even when inflammation was forcibly triggered.
Next, they tested an antibody that blocks CXCR3, a treatment that would protect the mice’s brain without removing tau. The mice were injected every five days for three and a half months, with the antibody never entering the brain tissue and instead nesting at the brain’s boundary. The results show that the mice had about half of the amount of T cells in their brains compared to animals that didn’t receive the antibody. On top of that, their brain’s memory-related regions were less damaged, and they performed better on a memory test.
But the mice’s tau clumps looked the same, despite their cognitive improvements. This suggests that treatment without touching the brain could be possible.
David M. Holtzman, MD, said, “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.”
However, more research is required on this method before it can be tested on humans, as well as the question of whether the treatment would work after a greater amount of neurodegeneration occurred. But Holtzman also suggests that existing T cell treatments, such as therapies used for multiple sclerosis and other autoimmune disorders, could be reevaluated and tested as a new way to treat Alzheimer’s.
