Washington University finds Alzheimer's brain damage in mice traces to lymph-node immune cells
Washington University School of Medicine researchers found that classical dendritic cells in peripheral lymph nodes activate the T cells that drive tau-related neurodegeneration in mice, even though the brain itself holds very few of these cells. Removing the dendritic cells left brain tau levels unchanged but sharply cut T cell buildup and preserved cognition. Senior author David Holtzman said future treatments might target the immune system outside the brain rather than crossing the blood-brain barrier.
Science··Evening
Dendritic cells outside the brain instruct the T cells driving damage
A Nature Neuroscience study from Washington University School of Medicine reports that CD8 T cells driving neuron loss in mice engineered to develop tau tangles take their activation instructions from classical dendritic cells in peripheral lymph nodes rather than from cells inside the brain. The brain itself holds very few of these dendritic cells, and the ones present do not interact with the disease-related T cells, the researchers found. When the team genetically eliminated dendritic cells from lymph nodes and other tissues outside the brain, the mice showed far fewer T cells accumulating in the brain and less of the expected brain damage, while their cognition remained normal, even though the abnormal tau protein itself did not decrease.[1], [2]
Lead researcher Hao Hu frames Alzheimer's as a whole-body process
Lead author Hao Hu, a postdoctoral fellow at Washington University Medicine, told Gizmodo that the result means researchers cannot study Alzheimer's by looking only inside the brain and need to examine the disease more systemically, since the whole body appears to be involved. The team's earlier work had already implicated T cell accumulation in the brain as a driver of damage, and a prior mouse study that blocked those T cells reduced inflammation and neurodegeneration. This new study traced where the T cells receive their activating signal, pointing to dendritic cells outside the brain rather than any comparable population within it. Hu said the approach could eventually let treatments target the peripheral immune system without needing to cross the blood-brain barrier, potentially delaying the disease even if it may not reverse it outright.[2]
Tau buildup may activate T cells through neck lymph nodes
Senior author David Holtzman, a Washington University professor of neurology, told Courthouse News that damage caused by tau buildup in the brain may release material that drains into lymph nodes in the neck, where dendritic cells activate the CD8 T cells that then migrate back toward the brain and contribute to further damage. Holtzman's laboratory had previously found that removing T cells from mice prevented much of the tau-associated brain damage, and the new study sought to determine where those T cells were being switched on in the first place. He said existing treatments that manipulate T cells could make the peripheral immune system a workable target for future Alzheimer's research, since a therapy may not need to reach the central nervous system to slow neurodegeneration. The findings, published in Nature Neuroscience, remain limited to mice, and the researchers plan next to test whether removing dendritic cells later in life still limits brain damage.[3], [1]
