Recent research uncovers an immune pathway outside the brain that triggers T cell activity, linking it to Alzheimer's disease and potential new therapies.
New findings from Washington University School of Medicine in St. Louis suggest a surprising external source that drives immune responses in Alzheimer's disease. Researchers identified that T cells, immune cells that usually protect the body, appear in elevated numbers in the brains of individuals afflicted with Alzheimer's and related conditions. Their accumulation contributes to neurodegeneration, but the origin and trigger for this influx have remained unclear.
In a study published on September 3 in Nature Neuroscience, scientists conducted experiments using mouse models and discovered that T cells are signaled from lymph nodes to enter the brain. When these signals were disrupted, neurodegeneration decreased significantly, revealing a new immune pathway that could help slow or even halt the damage associated with Alzheimer’s and primary tauopathies, which are diseases marked by abnormal tau protein accumulation.
David M. Holtzman, MD, who leads the research and serves as the Barbara Burton and Reuben M. Morriss III Distinguished Professor in Neurology at WashU, expressed that the implications of this study are profound. It highlights how a disease-related process can begin outside the brain, which may facilitate targeting treatments that are more accessible and comprehensible.
He remarked, "Normal treatment approaches often require delivery through the blood-brain barrier, yet we're discovering we might not need to administer drugs directly into the central nervous system to affect neurodegeneration." There is existing research involving T cell manipulation for other medical conditions that could potentially be applied to neurodegenerative diseases, but these avenues have yet to be fully explored.
Holtzman’s lab has previously illustrated that removing T cells from the brain can prevent significant neurodegeneration in mouse models that mimic tau-related damage. The next logical question was to trace the origins and activators of these immune cells. In this recent study, researchers, including postdoctoral fellow Hao Hu and co-senior author Jason Ulrich, evaluated the role of dendritic cells, which help T cells detect their targets.
Interestingly, classical dendritic cells type 1 (cDC1), which are crucial for T cell activation, are sparse in the brain. Those few present do not seem to interact with T cells that emerge in response to tau tangles. This observation suggested that dendritic cells and T cell activation processes were likely initiated outside the brain.
To investigate this, the team eliminated dendritic cells from lymph nodes and other sites in mice prone to developing tau tangles and neurodegeneration. The outcome was remarkable: elevated T cell levels, particularly CD8 T cells, significantly decreased in the brain. Alongside this reduction, the mice exhibited less brain damage while the levels of tau tangles remained unchanged, suggesting the connection is more about T cell activity than the presence of tau pathology itself.
Furthermore, cognitive abilities of the mice were preserved, implying that reducing T cell activity might slow cognitive decline in Alzheimer's patients, even when tau tangles persist. However, the exact signals prompting dendritic cells to activate T cells remain elusive. Holtzman speculates that tau-induced damage may release substances from brain cells, which travel to lymph nodes, prompting dendritic cells to present these as targets for T cell activation.
This immune pathway operating outside the brain presents various new therapeutic targets. Holtzman’s team is currently investigating whether intervening with dendritic cell activity in midlife, as tau tangles begin to form, can replicate the protective effects noted when dendritic cells were eliminated entirely in the study.
Moreover, there is an ongoing effort to discern the specific signal leading T cells to the brain; identifying this could provide an additional strategy for preventing the immune cells from reaching brain tissue and contributing to neuronal damage. Holtzman concluded, “Until recently, the immune response's role in neurodegenerative diseases was underestimated. Dendritic cells' involvement in these conditions is exciting. We’ve established their significance and the potential they hold as targets for future therapies.”
Materials provided by WashU Medicine. Note: Content may be edited for style and length.
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