Destructive immune cells tied to Alzheimer’s disease may get their marching orders from cells outside the brain rather than within it.
In mice, suppressing a small population of immune cells located in lymph nodes protects against neurodegeneration, researchers report September 3 in Nature Neuroscience. The findings raise the possibility of treating Alzheimer’s disease while bypassing the brain’s siege defenses.
For years, researchers have gone all in on efforts to remove toxic tangles of proteins like amyloid and tau from the brain as a way of halting Alzheimer’s, with limited success. But the immune system also plays an important role in neurodegeneration. What exactly that role is — protector or antagonist — has been unclear.
In 2023, neurologist David Holtzman and colleagues showed that immune system T cells accumulate around tau tangles — implying that they might cause damage. Halting these cells’ entry into the brain reduced inflammation, and also reduced neuronal damage, says Holtzman, of Washington University School of Medicine in St. Louis.
Still, it wasn’t known how these T cells accessed the brain in the first place. “A big question has been whether the T cells passively enter the brain or are primed … to do so,” says Rudolph Tanzi, a neurogeneticist at Harvard Medical School who wasn’t involved in the study.
During priming, T cells are ordered to rally and multiply. The generals that bark out these orders are called dendritic cells, which capture signatures of cellular threats called antigens and present them to T cell infantry.
No one had looked closely at what dendritic cells in lymph nodes were doing during neurodegenerative disease, Holtzman says. So in the new study, he and his colleagues compared two groups of mice engineered to have tau-linked neurodegeneration, one of which lacked dendritic cells.
In old age, mice without dendritic cells still had brains packed with tau. But compared with the other mice, they were protected against neurodegeneration and performed better on cognitive tasks like nest building.
They also had far fewer T cells in their brains. This suggests that tau tangles aren’t working alone in driving neurodegeneration, Holtzman says. “A lot of the damage that tau is causing is due to the inflammatory response that it’s eliciting.” The results would need to be replicated in human brains, he adds.
Despite this seemingly important role, the researchers found few dendritic cells in the mice’s brains. Instead, they detected threat-mimicking brain proteins traveling to the lymph nodes, where dendritic cells used them to rally T cells. The team bred mutant mice with demoted dendritic cell generals that could no longer give commands to T cells. These mice also had fewer T cells in their brains and better-preserved brain structures.
It isn’t practical to disable dendritic cells from birth in people at risk of Alzheimer’s. But Holtzman says his colleagues are working on cellular targets that could suppress them in adulthood. The real promise of the study may be a dementia treatment that bypasses the nervous system’s locked vault — the blood-brain barrier, Holtzman says. “If this panned out, potentially you wouldn’t have to get [therapeutics] into the brain.”
