Alzheimer’s damage may begin outside the brain

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.

Still, it wasn’t known how these T cells accessed the brain in the first place. 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. Alzheimer’s-like neurodegeneration can ravage a brain, as seen in the slice of a mouse’s brain at left.

The attack may be planned in the lymph nodes, new research suggests. The brain slice depicted on the right came from a mouse in which that early stage of attack was blocked. 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.