Scientists have uncovered evidence suggesting that neurodegeneration in Alzheimer’s disease may be driven by an immune response originating outside the brain, according to a study published in Sciencealert. While Alzheimer’s is traditionally viewed primarily as a brain disease, research published in Nature Neuroscience indicates that immune cells from beyond the brain could end up attacking it, causing significant damage.
Immune Response from Beyond the Brain Linked to Alzheimer’s Neurodegeneration
Previous research by the same team found that immune cells called T cells were implicated in the chain of events, appearing in abundance in the brains of mice that showed high levels of tau, one of the two key proteins associated with Alzheimer’s disease. Those earlier experiments demonstrated that eliminating or blocking the T cells in mice reduced neuronal damage, pointing to a potential new avenue for prospective treatments.
Until not that long ago, most people, including myself, did not think that the immune response was even involved in neurodegenerative diseases that are due to protein accumulation in the brain,
neurologist David Holtzman from Washington University in St. Louis, the senior author of both studies, told Sciencealert. We've shown they're important, and that they are a potential target for future therapy.
How Lymph Nodes and Dendritic Cells Direct T Cells to the Brain
While earlier research established the presence of T cells, it remained unclear why they were activated and how they found their way to the brain. The newly published findings, as reported by Newsweek, revealed that a specific form of immune cells known as CD8+ T cells can be directed to enter the brain through interactions involving another type of immune cell called dendritic cells, specifically cDC1 cells.
In experiments, cDC1 cells were rarely detected in the brain even during severe degeneration, leading researchers to hypothesize that signaling between cDC1s and CD8+ T cells occurs outside the brain. Separate experiments pointed to deep cervical lymph nodes in the neck as the activation site.
According to Holtzman’s team, tauopathy induces neuronal injury, resulting in the release of antigens that are captured by cDC1s. These cells then prime CD8+ T cells in the lymph nodes, which travel back upstream to the brain, ultimately causing neuroinflammation and neurodegeneration.
Potential New Targets for Future Alzheimer’s Therapies
Modifying cDC1 cells in mice did not substantially alter the amount of tau in the animals’ brains, suggesting that while neurodegeneration is related to tau accumulation, the immune response itself may serve as a primary driver of brain damage. Removing dendritic cells from lymph nodes and other locations in mice that would normally develop tau tangles produced striking results, as the mice maintained their cognitive abilities and suffered reduced brain damage.
Holtzman noted that human Alzheimer’s disease and primary tauopathies such as FTD, PSP, CBD, and CTE also feature an increased presence of T cells, including CD8 T cells, in areas containing tau pathology. Furthermore, genetic changes in the HLA locus in Alzheimer’s suggest T cell involvement.
Researchers emphasize that confirming a meaningful role in humans will require studies that directly test whether manipulating T cells improves patient outcomes. Potential immune-targeting therapies that could be explored include drugs suppressing T-cell entry into the brain, JAK-STAT inhibitors, checkpoint inhibitors, and T regulatory cell modulators. However, scientists state these approaches must first be evaluated in animal and cellular models to determine safety and effectiveness before advancing to human trials.
