Tau immunohistochemistry in acute brain injury
Abstract
Epidemiological studies have identified a history of head injury as a risk factor for Alzheimer's disease. However, the neuropathological mechanism underlying this relationship is as yet unclear. Neuronal cytoskeletal changes in the form of neurofibrillary tangles and neuropil threads have recently been demonstrated in young men who had sustained repetitive head injury and subsequently died in their 20s. In addition, recent experimental studies have found accumulation of tau within neuronal somata and damaged axons following diffuse brain injury. We hypothesized that tau‐immunoreactive tangles may be present in the brains of patients who died after a single acute blunt head injury. A total of 45 cases of fatal head injury were immunostained for tau. They comprised nine groups (n = 5 for each group) separated by age (0–19 years, 20–50 years, 50 + years) and survival time (< 24 h, 24 h−1 week, 1 week−1 month) and were compared with age‐matched controls. Subtle alterations in tau immunoreactivity, for example, in oligodendrocytes, were present in some head injury cases but not controls. However, neurofibrillary tangles did not appear more prevalent after traumatic brain injury (TBI) when compared with age‐matched controls. Although alterations in tau immunoreactivity may occur which warrant further study, neurofibrillary tangles were not more prevalent after a single fatal episode of TBI.
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Single TBI induces acute tau phosphorylation but not aggregation.
“Together, these studies demonstrate that single TBI induces acute tau phosphorylation but not aggregation.”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [166]
Cites
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Self-citationNeuronal cytoskeletal changes are an early consequence of repetitive head injury
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“The appearance of tau immunoreactivity was reported in cells around ischemic foci or brain injury.(31,32)”
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“Tau AT8 Thermo MN1020 1:1,500 Accumulation of tau in axons, oligodendrocytes, and neurons following TBI [28, 34]”
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“, 4 weeks after brain trauma, has not been detected [190].”
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“99 In a study of individuals surviving 1–47 years following a single TBI, the presence of widespread NFTs was noted in 34% of long-term TBI survivors, compared with a more focal tau distribution (i.e., entorhinal cortex and hippocampus) in only 9% of those who had not previously experienced a TBI.”
Lu, K. P., & Zhou, X. Z. (2024) · Science Signaling · doi:10.1126/scisignal.adi8743 · Cited by 11 · see citing works
“However, pathogenic tau pathology is not obvious acutely after brain injury ( 243 , 244 ), making it difficult to establish whether tauopathy is the end manifestation or an early driver of degenerative pathology after brain injury ( 237 , 241 ).”
BackgroundMany roads to Parkinson’s disease neurodegeneration: Head trauma- A road more traveled than we know?
Irwin, D. J., & Trojanowski, J. (2013) · Movement Disorders · doi:10.1002/mds.25551 · Cited by 11 · see citing works
Does Alzheimer's Disease Result from Attempts at Repair or Protection After Transient Stress?
Bissette, G. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1171 · Cited by 11 · see citing works
“…survival time intervals (less than 24 hours, 24 hours to one week, one week to one month) did not result in an increase in age-related neurofibrillary tangles but did alter tau phosphorylation status in oligo-dendrocytes in some cases of head injury, an effect that was never seen in controls [31].”
Butt, A., & Dinsdale, J. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2004.10.060 · Cited by 10
Srinivasan, G. R., & Brafman, D. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.813544 · Cited by 10 · see citing works
“…if at all, reported in acute survivors of TBI Frontiers in Aging Neuroscience | www.frontiersin.org 2 February 2022 | Volume 13 | Article 813544 (Smith et al., 2003; Ikonomovic et al., 2004) although alterations in tau immunoreactivity even in the absence of NFTs have been observed and warrant…”
BackgroundResultMafuika, S. N., Naicker, T., Harrichandparsad, R., & Lazarus, L. (2022) · Translational Research in Anatomy · doi:10.1016/j.tria.2022.100228 · Cited by 7 · see citing works
Unusually rapid and severe cognitive deterioration after mild traumatic brain injury
Kemp, S., Goulding, P., Spencer, J., & Mitchell, A. J. (2005) · Brain Injury · doi:10.1080/02699050500309353 · Cited by 8 · see citing works
“It is known that beta amyloid is increased after head injury, but neurofibrillary tangles are not [23, 24].”
BackgroundSoni, N., Medeiros, R., Alateeq, K., To, X. V., & Nasrallah, F. A. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.611451 · Cited by 8 · see citing works
Qiu, C., Li, Z., Leigh, D. A., Duan, B., Stucky, J. E., Kim, N., Xie, G., Lu, K. P., & Zhou, X. Z. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1343962 · Cited by 9 · see citing works
“…et al., 2013; Smith et al., 2013), but tau tangle pathology is not readily detectable acutely after closed head TBI in humans and mouse models (Smith et al., 2003; Yoshiyama et al., 2005; Flierl et al., 2009; Tran et al., 2011; Goldstein et al., 2012; Kane et al., 2012; Mannix et al., 2013;…”
BackgroundAltered Tau Kinase Activity in rTg4510 Mice after a Single Interfaced CHIMERA Traumatic Brain Injury
Cheng, W. H., Cheung, H., Kang, A., Fan, J., Cooper, J. G., Anwer, M., Barrón, C., Wilkinson, A., Hu, G., Yue, J., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119439 · Cited by 6 · see citing works
“A previous report comparing fatal TBI cases to controls (n = 5 per age group of <20 years, 20–50 years, >50 years) identified subtle tau immunoreactivity in glial cells during the acute period (<24 h to 1 month) after msTBI [5].”
BackgroundSmith, C. (2017) · Handbook of clinical neurology · doi:10.1016/b978-0-12-802395-2.00008-0 · Cited by 14 · see citing works
Self-citationTran, H. (2011) · Open Scholarship Institutional Repository (Washington University in St. Louis) · doi:10.7936/k7gb223z
“…accumulations of Aβ have been documented in approximately 30% of cases with severe TBI, but less frequently following mild, concussive TBI (Roberts et al., 1990; Roberts et al., 1991; Tokuda et al., 1991; Smith et al., 2003c; Ikonomovic et al., 2004; Uryu et al., 2007; Johnson et al., 2011).”
BackgroundChronic traumatic encephalopathy and the nucleus basalis of Meynert.
Mufson, E., Kelley, C. M., & Perez, S. E. (2021) · Handbook of Clinical Neurology · doi:10.1016/b978-0-12-819973-2.00002-2 · Cited by 4 · see citing works
Trajectories of blood-based protein biomarkers in chronic traumatic brain injuryPreprint
Hicks, A. J., Plourde, J., Selmanovic, E., de Souza, N. L., Blennow, K., Zetterberg, H., & Dams-O’Connor, K. (2025) · medRxiv · doi:10.1101/2025.02.16.25322303 · Cited by 2 · see citing works
Injury-induced tau pathology promotes aggressive behavior in Drosophila without neurodegeneration
Maxson, R., Smoyer, C. J., Hampton, M. F., Shen, Y., Wiese, K., Yee, C., Singh, A., Funtila, A., McKenney, R. J., & Ori-McKenney, K. M. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2600627123 · Cited by 1 · see citing works
Hicks, A. J., Selmanovic, E., Pruyser, A., Trentman, C. R., Klein, J. C., Wilkey, K., Escalón, M., Bernal-Fernández, N., Yew, B., & Dams-O'Connor, K. (2025) · Neurotrauma Reports · doi:10.1177/08977151251362180 · Cited by 1 · see citing works
“11,12 33 Now, brain tissue is increasingly available in large chronic TBI cohorts, 34,35 creating opportunities to identify mechanistic pathological processes involved in chronic TBI and PTND. Clinicopathological correlations, the process of identifying associations between clinical symptoms…”
Butler, T. (2022) · Journal of Neurotrauma · doi:10.1089/neu.2022.0505 · Cited by 1 · see citing works
“23 We recently reported possible positron emission tomography (PET)-measured tauopathy in one subject with a history of repeated SRC who sustained a complicated mild TBI while playing a sport but not in subjects who sustained similar TBIs outside of sport.”
Nanocarriers and Intracellular Transport: Moving Along the Cytoskeletal Matrix
Woolf, N. J., Priel, A., & Tuszyński, J. A. (2009) · Biological and medical physics series · doi:10.1007/978-3-642-03584-5_4 · Cited by 1 · see citing works
Li, Z., Li, Y., Liu, R., Zhu, Y. M., Wang, R., Lu, K. P., & Zhou, X. Z. (2026) · Cells · doi:10.3390/cells15181650
“For many years, the molecular link between acute traumatic brain injury and delayed neurodegeneration lacked clarity largely because overt tau pathology is not readily detectable in human brains after fatal acute brain injury [101].”
Injury-induced tau pathology promotes aggressive behavior in Drosophila without neurodegenerationPreprint
Maxson, R., Smoyer, C. J., Hampton, M. F., Shen, Y., Wiese, K., Yee, C., Singh, A., Funtila, A., Mckenney, R. J., & Ori-McKenney, K. M. (2025) · bioRxiv · doi:10.1101/2025.11.22.689595
“Critical gaps remain in understanding not only the physiological function of tau, but how acute tau phosphorylation following injury affects neuronal function and behavior before neurodegeneration occurs 9,17 .”
InfluentialDegenerative and cognitive diseases.
Cid, R. C. C. (2023) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001201
Altered tau in rTg4510 mice after a single interfaced CHIMERA traumatic brain injuryPreprint
Cheng, W. H., Cheung, H., Kang, A., Fan, J., Cooper, J. G., Anwer, M., Barrón, C., Wilkinson, A., Hu, G., Yue, J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.01.506145
Havlicek, D. F., Furhang, R., Nikulina, E., Smith-Salzberg, B., Lawless, S., Sevarin, S. A., Mallaboeva, S., Nayab, F., Seifert, A. C., Crary, J. F., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.19.492705
“Smith et al. reported increased Tau expression in oligodendrocytes less than 1 month after a single TBI in humans, yet did not report an increase in Tau expression in neurons relative to non-TBI controls (Smith et al., 2003).”
BackgroundResultInfluentialVictoroff, J. (2019) · Cambridge University Press eBooks · doi:10.1017/9781139696432.009
Pathological Tau as a Cause, and Consequence, of Cellular Dysfunction
Meier, S. E. (2019) · UKnowledge (University of Kentucky) · doi:10.13023/etd.2019.368
“Tau pathology is observed in human brain tissue after TBI [208, 209] and elevated tau levels in serum and cerebrospinal fluid after injury correlate with worsened outcomes [210, 211].”
BackgroundNanolipidic Carriers as Potential Drug Delivery Vehicles in Alzheimer’s Disease
Talegaonkar, S., Gautam, N., Varshney, V., Sharma, S., & Bhattacharyya, A. (2019) · Springer eBooks · doi:10.1007/978-3-030-30930-5_13
- Authors
- Smith, C., Graham, D. I., Murray, L. S., & Nicoll, J. A. R.
- Affiliations
- Western General Hospital (GB)
- Southern General Hospital (GB)
- Western Infirmary (GB)
- Southampton General Hospital (GB)
- Corresponding author
- Smith, C.
- Venue
- Neuropathology and Applied Neurobiology
- Publisher
- Wiley
- Published
- 2003-10
- Volume
- 29
- Issue
- 5
- Pages
- 496-502
- ISSN
- 0305-1846 (ISSN-L)
- 1365-2990
- OpenAlex
- W1998068768
- Cited by
- 110
- References
- 0
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 8 · 2021: 6 · 2020: 1 · 2019: 9 · 2018: 4 · 2017: 5 · 2016: 9 · 2015: 6 · 2014: 10 · 2013: 9 · 2012: 3
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropathology and Applied Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- tau protein, traumatic brain injury, neurofibrillary tangles, neuropil threads, acute head injury, Alzheimer's disease risk, repetitive head injury, diffuse brain injury, oligodendrocytes, fatal head injury
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Brain Injuries, Child, Child, Preschool, Humans, Immunohistochemistry, Infant, Middle Aged, Neurofibrillary Tangles, tau Proteins, Neuropil Threads
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