Journal article
Repeated head trauma causes neuron loss and inflammation in young athletes
Nature (London), Vol.647(8088), pp.228-237
11/06/2025
DOI: 10.1038/s41586-025-09534-6
PMCID: PMC12589125
PMID: 40963024
Abstract
Repetitive head impacts (RHIs) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE). Currently, CTE can only be diagnosed after death and the events that trigger initial hyperphosphorylated tau (p-tau) deposition remain unclear. Furthermore, the symptoms endorsed by young individuals are not fully explained by the extent of p-tau deposition, severely hampering therapeutic interventions. Here we observed a multicellular response prior to the onset of CTE p-tau pathology that correlates with number of years of RHI exposure in young people (less than 51 years of age) with RHI exposure, the majority of whom played American football. Leveraging single-nucleus RNA sequencing of tissue from 8 control individuals, 9 RHI-exposed individuals and 11 individuals with low-stage CTE, we identify SPP1-expressing inflammatory microglia, angiogenic and inflamed endothelial cells, astrocytosis and altered synaptic gene expression in those exposed to RHI. We also observe a significant loss of cortical sulcus layer 2/3 neurons independent of p-tau pathology. Finally, we identify TGFβ1 as a potential signal that mediates microglia-endothelial cell cross talk. These results provide robust evidence that multiple years of RHI is sufficient to induce lasting cellular alterations that may underlie p-tau deposition and help explain the early pathogenesis in young former contact sport athletes. Furthermore, these data identify specific cellular responses to RHI that may direct future identification of diagnostic and therapeutic strategies for CTE.
Details
- Title: Subtitle
- Repeated head trauma causes neuron loss and inflammation in young athletes
- Creators
- Morgane L M D Butler - Boston UniversityNida Pervaiz - Boston UniversityKerry Breen - Boston UniversitySamantha Calderazzo - Boston UniversityPetra Ypsilantis - VA Boston Healthcare SystemYichen Wang - Boston UniversityJulia Cammasola Breda - Boston UniversitySarah Mazzilli - Boston UniversityRaymond Nicks - VA New England Healthcare SystemElizabeth Spurlock - VA New England Healthcare SystemMarco M Hefti - University of IowaKimberly L Fiock - University of IowaBertrand R Huber - VA Boston Healthcare SystemVictor E Alvarez - VA Boston Healthcare SystemThor D Stein - Boston UniversityJoshua D Campbell - Boston UniversityAnn C McKee - Boston UniversityJonathan D Cherry - Boston University
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.647(8088), pp.228-237
- DOI
- 10.1038/s41586-025-09534-6
- PMID
- 40963024
- PMCID
- PMC12589125
- NLM abbreviation
- Nature
- ISSN
- 1476-4687
- eISSN
- 1476-4687
- Publisher
- NATURE PORTFOLIO
- Grant note
- NINDS: U54NS115266, RF1NS143015 NIH: U19-AG068753 NIA: AG057902, AG062348, AG090553 National Institute of Aging Boston University Alzheimer's Disease Research Center: P30AG072978, BX002466 Department of Veterans Affairs Career Development Award: BX004349 BLRD Merit Award: I01BX005933
This work was supported by grant funding from: NINDS (F31NS132407), NIH (U19-AG068753), NIA (AG057902, AG062348 and AG090553), NINDS (U54NS115266 and RF1NS143015), National Institute of Aging Boston University Alzheimer's Disease Research Center (P30AG072978), Department of Veterans Affairs Biorepository (BX002466), the Department of Veterans Affairs Career Development Award (BX004349) and BLRD Merit Award (I01BX005933). The views, opinions, and/or findings contained in this article are those of the authors and should not be construed as an official Veterans Affairs or Department of Defense position, policy, or decision, unless so designated by other official documentation. Funders did not have a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. We would like to extend our gratitude to the brain donors and their families without whom this work would be impossible. The authors thank the clinical and neuropathology teams at the BU CTE Center who perform clinical interviews with next of kin and routine tissue processing and D. Rosene, B. Conner and S. Horowitz for methodological support, and the Boston University Single Cell Sequencing Core for their assistance in performing the experiments.
- Language
- English
- Electronic publication date
- 09/17/2025
- Date published
- 11/06/2025
- Academic Unit
- Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9984963630602771
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