Induction of a transmissible tau pathology by traumatic brain injury
Open accessAbstract
Traumatic brain injury is a risk factor for subsequent neurodegenerative disease, including chronic traumatic encephalopathy, a tauopathy mostly associated with repetitive concussion and blast, but not well recognized as a consequence of severe traumatic brain injury. Here we show that a single severe brain trauma is associated with the emergence of widespread hyperphosphorylated tau pathology in a proportion of humans surviving late after injury. In parallel experimental studies, in a model of severe traumatic brain injury in wild-type mice, we found progressive and widespread tau pathology, replicating the findings in humans. Brain homogenates from these mice, when inoculated into the hippocampus and overlying cerebral cortex of naïve mice, induced widespread tau pathology, synaptic loss, and persistent memory deficits. These data provide evidence that experimental brain trauma induces a self-propagating tau pathology, which can be transmitted between mice, and call for future studies aimed at investigating the potential transmissibility of trauma associated tau pathology in humans.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Single, severe TBI is associated in humans and mouse models with widespread hyperphosphorylated tau pathology, and mice with APOE ε4 compared with APOE ε3 allele have more hippocampal hyperphosphorylated tau after TBI.
“Single, severe TBI is associated in humans, and mouse models, with widespread hyperphosphorylated tau pathology, and mice with APOE ε4 compared to APOE ε3 allele have more hippocampal hyper-phosphorylated tau after TBI.64, 65”
From Dementia prevention, intervention, and care: 2020 report of the Lancet Commission (2020) · cites this paper as [64]
The Discussion and Results report widespread phosphorylated tau pathology in some people surviving a single moderate or severe TBI and progressive spread after severe TBI in wild-type mice. Our copy does not report an APOE ε4 versus ε3 comparison or greater hippocampal phosphorylated tau in ε4 mice after TBI (searched: APOE, apolipoprotein E, ε4 and ε3). (LLM, conf=0.90)
Experimental — accuracy not yet measuredSustaining even a single traumatic brain injury can result in progressive neurofibrillary tangle formation that is more extensive and severe than what is expected with normal aging.
“For instance, sustaining even a single TBI can result in progressive NFT formation that is more extensive and severe than what is expected with normal aging (Johnson et al., 2012; Zanier et al., 2018).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Zanier et al., 2018
The Results report more extensive neurofibrillary tangles and other tau pathology in survivors of a single moderate or severe TBI than in age-matched controls. Progressive spread was observed in mice after severe TBI, but the Discussion says the human data could not establish an association between time since injury and the extent of tau pathology. The claim therefore overextends the evidence for progressive tangle formation in humans and does not specify injury severity. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Transmission and spreading of tauopathy in transgenic mouse brain
Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1901 · Cited by 1,803 · see citing works
Propagation of Tau Pathology in a Model of Early Alzheimer's Disease
de Calignon, A., Polydoro, M., Suárez-Calvet, M., William, C., Adamowicz, D. H., Kopeikina, K. J., Pitstick, R., Sahara, N., Ashe, K. H., Carlson, G. A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.033 · Cited by 1,427 · see citing works
Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football
Mez, J., Daneshvar, D. H., Kiernan, P. T., Abdolmohammadi, B., Alvarez, V. E., Huber, B. R., Alosco, M. L., Solomon, T. M., Nowinski, C. J., McHale, L., et al. (2017) · JAMA · doi:10.1001/jama.2017.8334 · Cited by 1,098 · see citing works
the TBI/CTE group, McKee, A. C., Cairns, N. J., Dickson, D. W., Folkerth, R. D., Dirk Keene, C., Litvan, I., Perl, D. P., Stein, T. D., Vonsattel, J.-P., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1515-z · Cited by 885 · see citing works
Aging-related tau astrogliopathy (ARTAG): Harmonized evaluation strategy
Kovacs, G. G., Ferrer, I., Grinberg, L. T., Alafuzoff, I., Attems, J., Budka, H., Cairns, N. J., Crary, J. F., Duyckaerts, C., Ghetti, B., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1509-x · Cited by 532 · cited 1× · see citing works
“One further TBI case, an 87-year-old male with a 5-year survival following a road traffic accident, showed clusters of P-tau immunoreactive subpial astrocytes in the medial temporal lobe, consistent with ageing-related tau astrogliopathy (Kovacs et al., 2016).”
BackgroundGuo, J. L., Narasimhan, S., Changolkar, L., He, Z., Stieber, A., Zhang, B., Gathagan, R. J., Iba, M., McBride, J. D., Trojanowski, J. Q., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20160833 · Cited by 440 · see citing works
Neuronal cytoskeletal changes are an early consequence of repetitive head injury
Geddes, J. F., Vowles, G. H., Nicoll, J. A. R., & Révész, T. (1999) · Acta Neuropathologica · doi:10.1007/s004010051066 · Cited by 323 · see citing works
Iba, M., McBride, J. D., Guo, J. L., Zhang, B., Trojanowski, J. Q., & Lee, V. M.-Y. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1458-4 · Cited by 223 · see citing works
Goedert, M., & Spillantini, M. G. (2017) · Molecular Brain · doi:10.1186/s13041-017-0298-7 · Cited by 213 · see citing works
Prion-like Properties of Tau Protein: The Importance of Extracellular Tau as a Therapeutic Target
Holmes, B. B., & Diamond, M. I. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.549295 · Cited by 202 · see citing works
Repetitive blast exposure in mice and combat veterans causes persistent cerebellar dysfunction
Meabon, J. S., Huber, B. R., Cross, D. J., Richards, T. L., Minoshima, S., Pagulayan, K. F., Li, G., Meeker, K. D., Kraemer, B. C., Petrie, E. C., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa9585 · Cited by 138 · see citing works
Yoshiyama, Y., Uryu, K., Higuchi, M., Longhi, L., Hoover, R., Fujimoto, S., McIntosh, T., Lee, V. M.-Y., & Trojanowski, J. Q. (2005) · Journal of Neurotrauma · doi:10.1089/neu.2005.22.1134 · Cited by 133 · see citing works
Gerson, J., Castillo-Carranza, D. L., Sengupta, U., Bodani, R., Prough, D. S., DeWitt, D. S., Hawkins, B. E., & Kayed, R. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2015.4262 · Cited by 94 · cited 1× · see citing works
“A few studies reported formation of tau aggregates shortly after severe TBI in rats (Hawkins et al., 2013; Gerson et al., 2016), with only one study showing persistent tau pathology in wild-type mice (Kondo et al.”
BackgroundZanier, E. R., Marchesi, F., Ortolano, F., Perego, C., Arabian, M., Zoerle, T., Sammali, E., Pischiutta, F., & De Simoni, M.-G. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2015.4041 · Cited by 94 · cited 2× · see citing works
“refinement, reduction, and replacement, minimizing the numbers of mice, while using biostatistics to optimize mouse numbers (as in our previously published peer-reviewed work using the mouse TBI model (Zanier et al., 2016) and prion inoculation in mice (Bouybayoune et al.”
MethodSelf-citationBouybayoune, I., Mantovani, S., Del Gallo, F., Bertani, I., Restelli, E., Comerio, L., Tapella, L., Baracchi, F., Fernández-Borges, N., Mangieri, M., et al. (2015) · PLOS Pathogens · doi:10.1371/journal.ppat.1004796 · Cited by 81 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 36
- Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H, et al. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol 2014; 127: 667-83.
- Braak H, Braak E. Staging of Alzheimer's disease-related neurofibril- lary changes. Neurobiol Aging 1995; 16: 271-8.
- Chiesa R. The elusive role of the prion protein and the mechanism of toxicity in prion disease. PLoS Pathog 2015; 11: e1004745.
- Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 2013; 110: 9535-40.
- Goedert M, Masuda-Suzukake M, Falcon B. Like prions: the propa- gation of aggregated tau and alpha-synuclein in neurodegeneration. Brain 2017; 140: 266-78.
- Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: se- quences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 1989; 3: 519-26.
- Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, et al. Chronic traumatic encephalopathy in blast-exposed mili- tary veterans and a blast neurotrauma mouse model. Sci Transl Med 2012; 4: 134ra60.
- Hawkins BE, Krishnamurthy S, Castillo-Carranza DL, Sengupta U, Prough DS, Jackson GR, et al. Rapid accumulation of endogenous tau oligomers in a rat model of traumatic brain injury: possible link between traumatic brain injury and sporadic tauopathies. J Biol Chem 2013; 288: 17042-50.
- Hay J, Johnson VE, Smith DH, Stewart W. Chronic traumatic enceph- alopathy: the neuropathological legacy of traumatic brain injury. Annu Rev Pathol 2016; 11: 21-45.
- Heise C, Schroeder JC, Schoen M, Halbedl S, Reim D, Woelfle S, et al. Selective localization of shanks to VGLUT1-positive excitatory syn- apses in the mouse hippocampus. Front Cell Neurosci 2016; 10: 106.
- Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic Tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci 2013; 33: 1024-37.
- Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, et al. Impairment of glymphatic pathway function promotes Tau path- ology after traumatic brain injury. J Neurosci 2014; 34: 16180-93.
- Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 2013; 136: 28-42.
- Johnson VE, Stewart W, Smith DH. Widespread and amyloid-b pathology many years after a single traumatic brain injury in humans. Brain Pathol 2012; 22: 142-9.
- Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM, et al. Tau prion strains dictate patterns of cell path- ology, progression rate, and regional vulnerability in vivo. Neuron 2016; 92: 796-812.
- Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010; 8: e1000412.
- Kondo A, Shahpasand K, Mannix R, Qiu J, Moncaster J, Chen CH, et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 2015; 523: 431-6.
- Kovacs GG. Invited review: neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 2015; 41: 3-23.
- Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Guerrero- Munoz MJ, Kiritoshi T, Neugebauer V, et al. Alzheimer brain- derived tau oligomers propagate pathology from endogenous tau. Sci Rep 2012; 2: 700.
- Makinde HM, Just TB, Cuda CM, Perlman H, Schwulst SJ. The role of microglia in the etiology and evolution of chronic traumatic en- cephalopathy. Shock 2017; 48: 276-83.
- McKee AC, Daneshvar DH, Alvarez VE, Stein TD. The neuropathol- ogy of sport. Acta Neuropathol 2014; 127: 29-51.
- Mudher A, Colin M, Dujardin S, Medina M, Dewachter I, Alavi Naini SM, et al. What is the evidence that tau pathology spreads through prion-like propagation? Acta Neuropathol Commun 2017; 5: 99.
- Narasimhan S, Guo JL, Changolkar L, Stieber A, McBride JD, Silva LV, et al. Pathological tau strains from human brains recapitulate the diversity of tauopathies in non-transgenic mouse brain. J Neurosci 2017; 37: 11406-23.
- Ojo JO, Mouzon B, Algamal M, Leary P, Lynch C, Abdullah L, et al. Chronic repetitive mild traumatic brain injury results in reduced cerebral blood flow, axonal injury, gliosis, and increased T-Tau and Tau oligomers. J Neuropathol Exp Neurol 2016; 75: 636-55.
- Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. San Diego, CA: Academic Press; 2004.
- Petry FR, Pelletier J, Bretteville A, Morin F, Calon F, He ´bert SS, et al. Specificity of anti-tau antibodies when analyzing mice models of Alzheimer's disease: problems and solutions. PLoS One 2014; 9: e94251.
- Pischiutta F, Micotti E, Hay JR, Marongiu I, Sammali E, Tolomeo D, et al. Single severe traumatic brain injury produces progressive path- ology with ongoing contralateral white matter damage one year after injury. Exp Neurol 2018; 300: 167-78.
- Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982; 216: 136-44.
- Prusiner SB. Cell biology. A unifying role for prions in neurodegen- erative diseases. Science 2012; 336: 1511-13.
- Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 2014; 82: 1271-88.
- Sekino Y, Koganezawa N, Mizui T, Shirao T. Role of Drebrin in synaptic plasticity. In: Drebrin. Tokyo: Springer; 2017. p. 183-201.
- Senatore A, Colleoni S, Verderio C, Restelli E, Morini R, Condliffe SB, et al. Mutant PrP suppresses glutamatergic neurotransmission in cerebellar granule neurons by impairing membrane delivery of VGCC alpha(2)delta-1 subunit. Neuron 2012; 74: 300-13.
- Smith DH, Soares HD, Pierce JS, Perlman KG, Saatman KE, Meaney DF, et al. A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects. J Neurotrauma 1995; 12: 169-78.
- Tran HT, LaFerla FM, Holtzman DM, Brody DL. Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra- axonal amyloid-beta accumulation and independently accelerates the development of tau abnormalities. J Neurosci 2011a; 31: 9513-25.
- Tran HT, Sanchez L, Esparza TJ, Brody DL. Distinct temporal and anatomical distributions of amyloid-b and tau abnormalities follow- ing controlled cortical impact in transgenic mice. PLoS One 2011b; 6: e25475.
- Woerman AL, Aoyagi A, Patel S, Kazmi SA, Lobach I, Grinberg LT, et al. Tau prions from Alzheimer's disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc Natl Acad Sci USA 2016; 113: E8187-96.
Cited by
Sorted by citations
Dementia prevention, intervention, and care: 2020 report of the Lancet Commission
Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., Brayne, C., Burns, A., Cohen-Mansfield, J., Cooper, C., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30367-6 · Cited by 10,430 · see citing works
RetractedMechanisms of secretion and spreading of pathological tau protein
Brunello, C. A., Merezhko, M., Uronen, R.-L., & Huttunen, H. J. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03349-1 · Cited by 304 · see citing works
“AD Alzheimer’s disease AGD Argyrophylic grain disease CBD Corticobasal degeneration CSF Cerebrospinal fluid EM Electron microscopy ER Endoplasmic reticulum FGF2 Fibroblast growth factor 2 FTD Frontotemporal dementia FTDP-17 Frontotemporal dementia with Parkinsonism in chromosome 17 GAG Glycosaminoglycan HSPG Heparin s…”
BackgroundRole of tau protein in Alzheimer’s disease: The prime pathological player
Muralidar, S., Ambi, S. V., Sekaran, S., Thirumalai, D., & Palaniappan, B. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.07.327 · Cited by 278 · see citing works
Intersection of pathological tau and microglia at the synapse
Vogels, T., Murgoci, A.-N., & Hromádka, T. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0754-y · Cited by 197 · see citing works
Lee, E. B., Kinch, K., Johnson, V. E., Trojanowski, J. Q., Smith, D. H., & Stewart, W. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02030-y · Cited by 157 · see citing works
Self-citationIverson, G. L., Luoto, T. M., Karhunen, P. J., & Castellani, R. J. (2019) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlz045 · Cited by 63 · see citing works
Seizures are a druggable mechanistic link between TBI and subsequent tauopathy.
Alyenbaawi, H., Kanyo, R., Locskai, L. F., Kamali-Jamil, R., DuVal, M. G., Bai, Q., Wille, H., Burton, E. A., & Allison, W. T. (2021) · eLife · doi:10.7554/elife.58744 · Cited by 40 · see citing works
Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms
Hwang, K., Vaknalli, R. N., Addo-Osafo, K., Vicente, M., & Vossel, K. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.903973 · Cited by 35 · see citing works
Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease
Chimal-Juárez, E., Patel, H., Jury-Garfe, N., Dabin, L. C., Vidal, R., Kim, J., & Lasagna-Reeves, C. A. (2026) · bioRxiv · doi:10.64898/2026.05.12.724684
- Authors
- Zanier, E. R., Bertani, I., Sammali, E., Pischiutta, F., Chiaravalloti, M. A., Vegliante, G., Masone, A., Corbelli, A., Smith, D. H., Menon, D. K., Stocchetti, N., Fiordaliso, F., De Simoni, M.-G., Stewart, W., & Chiesa, R.
- Affiliations
- Mario Negri Institute for Pharmacological Research (IT)
- University of Pennsylvania (US)
- University of Cambridge (GB)
- University of Milan (IT)
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
- Institute of Neuroscience and Psychology, University of Glasgow, Glasgow G12 8QQ, UK
- Corresponding author
- Zanier, Elisa R
- Chiesa, Roberto
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-08-01
- Volume
- 141
- Issue
- 9
- Pages
- 2685-2699
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC6113646
- OpenAlex
- W2886141281
- Cited by
- 136
- References
- 15
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 14 · 2023: 18 · 2022: 19 · 2021: 21 · 2020: 37 · 2019: 10 · 2018: 3
- FWCI
- 12.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- National Institutes of Health (NIH NS094003, NS038104)
- NHS Research Scotland Career- Researcher Fellowship
- Alzheimer’s Association (AARG-18-532633)
- National Institute for Health Research
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- traumatic brain injury, tauopathy, hyperphosphorylated tau, chronic traumatic encephalopathy, synaptic loss, memory impairment, neurodegeneration risk
- MeSH terms
- Brain Injuries, Traumatic, Aged, Aged, 80 and over, Animals, Brain, Brain Concussion, Cerebral Cortex, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Middle Aged, Phosphorylation, tau Proteins, Neurodegenerative Diseases, Tauopathies, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
