A study found that immune cells that drive neurodegeneration, the progressive damage and loss of nerve cells, originate in the body’s lymph nodes.
In mice whose brains accumulate clumps of tau protein, researchers found a way to protect nerve cells without clearing away those clumps. They interrupted an immune response directed from outside the brain, where lymph nodes give instructions to T cells, immune cells that normally help defend the body.
The Washington University School of Medicine in St. Louis team found that blocking those instructions from birth protected the mice against brain damage and preserved their cognitive abilities. The results point to a possible treatment strategy for Alzheimer’s disease and related tau disorders that targets immune activity beyond the brain itself.
The study was published in Nature Neuroscience. Along with Alzheimer’s, tau accumulates in a group of disorders called primary tauopathies. Whether the approach can protect against damage when started later in life is still being investigated.
A target beyond the blood-brain barrier
Targeting cells outside the brain could help researchers avoid a major obstacle in drug development. The blood-brain barrier, a tightly controlled boundary between the bloodstream and brain tissue, limits the entry of many substances, including medicines.
“One of the issues in developing treatments for neurological diseases is that you need to engineer your treatment so that it gets into the brain and past the blood-brain barrier, but we might not actually need to get the drugs into the central nervous system to mitigate neurodegeneration,” said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor in WashU Medicine’s Department of Neurology. “There are lots of ways to manipulate T cells that have been studied extensively and that are approved treatments for other diseases, but many haven’t yet been explored for neurodegenerative diseases.”
Tracing the cells that instruct T cells
The brains of people with Alzheimer’s and related disorders contain far more T cells than healthy brains. In a previous study, Holtzman’s team found that eliminating T cells in the brain prevented much of the nerve cell damage in mice modeling the effects of tau accumulation. That left unanswered where the T cells came from and what directed them to the brain.
Certain T cells rely on another type of immune cell, called a dendritic cell, to identify molecular targets for attack. The researchers focused on classical dendritic cells type 1, or cDC1. Very few of these cells reside in the brain, and those present did not appear to interact with the T cells that accumulated after tau tangles developed. The cells giving the instructions therefore seemed likely to be elsewhere.
The team included first author Hao Hu, PhD, a postdoctoral fellow, and co-senior author Jason Ulrich, PhD, a professor of neurology. Working with collaborators, they eliminated dendritic cells from lymph nodes and other locations in mice that ordinarily develop tau tangles and neurodegeneration.
Without those dendritic cells, the usual rise in brain T cells, particularly a subset called CD8 T cells, disappeared, along with the associated brain damage. The mice retained their cognitive abilities despite unchanged levels of tau tangles. These results suggest that interrupting T cell activity may help slow or reduce cognitive decline associated with Alzheimer’s, although the demonstrated protection was in mice.
The immune trigger remains unknown
What initially prompts the dendritic cells to activate T cells remains unknown. Holtzman suspects that tau-related damage releases material from brain cells that then travels to lymph nodes in the neck. Dendritic cells may identify that material as something T cells should attack.
“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,” Holtzman said. “That these dendritic cells are involved in neurodegenerative disease is exciting; we’ve shown they’re important, and that they are a potential target for future therapy.”
His team is now testing whether disrupting dendritic cell function in midlife, around the onset of tau tangles, can provide the same protection as blocking it from birth. The researchers are also trying to identify the specific signal that guides T cells to the brain so they can explore ways to block it.
Reference: “Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration” by Hao Hu, Peter Bor-Chian Lin, Carisa Zeng, Yongyi Li, Megan E. Bosch, Joshua T. Emmerson, Prabal Sharma, Ray A. Ohara, Wendy Dong, Tong Wu, Siling Du, Wenqing Gao, Hong Jiang, Liya Yuan, Xin Bao, Shasha Li, Anthony N. Vomund, Petra Erdmann-Gilmore, Yichen Gu, Miwei Hu, Jonathan Nulman, Timothy M. Miller, Wayne M. Yokoyama, Cheryl F. Lichti, Jeffrey Milbrandt, Richard J. Perrin, Jonathan Kipnis, Maxim N. Artyomov, Kenneth M. Murphy, Jason D. Ulrich and David M. Holtzman, 3 September 2026, Nature Neuroscience.
DOI: 10.1038/s41593-026-02427-5
This work was supported by a Carol and Gene Ludwig Award for Neurodegeneration Research, National Institute of Health grant AG085374, NS090934, the GHR Foundation, the JPB Foundation, Cure Alzheimer’s Fund, Rainwater Charitable Foundation, Carol and Gene Ludwig Family Foundation, the Knight Alzheimer’s Disease Research Center Neuropathology Core (NIH P30AG066444, NIH P01 AG03991, and NIH P01AG026276), NIH/NIA R37AG034113 and R01AG078667, Alzheimer’s Association Research Fellowship AARF -23-1142708, and NIH grant R01-AI129545. We are grateful to E. Reiman, G. Serrano and T. Beach of the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human primary tauopathy brain tissue. The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. Meningeal tissues were provided and funded by Washington University Translational Human Neurodegenerative Disease Research (THuNDR) Laboratory for Knight ADRC research.
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