Tau oligomers derived from traumatic brain injury cause cognitive impairment and accelerate onset of pathology in htau mice
Open accessAbstract
Tau aggregation is a pathological feature of numerous neurodegenerative disorders and has also been shown to occur under certain conditions of traumatic brain injury (TBI). Currently, no effective treatments exist for the long-term effects of TBI. In some cases, TBI not only induces cognitive changes immediately post-injury, but also leads to increased incidence of neurodegeneration later in life. Growing evidence from our lab and others suggests that the oligomeric forms of tau initiate the onset and spread of neurodegenerative tauopathies. Previously, we have shown increased levels of brain-derived tau oligomers in autopsy samples from patients diagnosed with Alzheimer's disease. We have also shown similar increases in tau oligomers in animal models of neurodegenerative diseases and TBI. In the current study, we evaluated the presence of tau oligomers in blast-induced TBI. To test the direct impact of TBI-derived tau oligomer toxicity, we isolated tau oligomers from brains of rats that underwent either a blast- or a fluid percussion injury–induced TBI. Oligomers were characterized biochemically and morphologically and were then injected into hippocampi of mice overexpressing human tau (Htau). Mice were cognitively evaluated and brains were collected for immunological analysis after testing. We found that tau oligomers form as a result of brain injury in two different models of TBI. Additionally, these oligomers accelerated onset of cognitive deficits when injected into brains of Htau mice. Tau oligomer levels increased in the hippocampal injection sites and cerebellum, suggesting that tau oligomers may be responsible for seeding the spread of pathology post-TBI. Our results suggest that tau oligomers play an important role in the toxicity underlying TBI and may be a viable therapeutic target.
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Tau oligomers are neurotoxic and contribute to tau spreading throughout the brain.
“supporting the notion that tau oligomers are neurotoxic and contribute to tau spreading throughout the brain (180).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [180]
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“102 Collectively, the pathological changes in A b and tau may represent NEUROTROPHIC FACTORS POST-TBI a foundation for the long-term development of dementia.”
Tubulin‐Binding Region Modulates Cholesterol‐Triggered Aggregation of Tau Proteins
Ali, A., Matveyenka, M., Pickett, D. N., Rodriguez, A., & Kurouski, D. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.16294 · Cited by 10 · see citing works
“These toxic β-sheet–rich aggregates exhibit high structural and morphological variability (Eisenberg and Sawaya 2017; Falcon et al. 2019; Gerson et al. 2016; Grundke-Iqbal et al. 1986; Hoshi et al. 2003).”
Gu, W., Bai, Y.-N., Cai, J., Mi, H., Bao, Y.-C., Zhao, X., Lu, C., Zhang, F.-C., Li, Y.-H., & Lu, Q. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1061039 · Cited by 10 · see citing works
“Increases in Aβ protein deposition and tau neurofibrillary tangles were observed both ipsilaterally and contralaterally to the injury site (Gerson et al., 2016; Meabon et al., 2016; Grant et al., 2018; Zanier et al., 2018).”
BackgroundRetractedKatsumoto, A., Kokiko‐Cochran, O. N., Bemiller, S. M., Xu, G., Ransohoff, R. M., & Lamb, B. T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.978423 · Cited by 10 · see citing works
“Frontiers in Immunology 02 phosphorylation (3, 5, 7).”
BackgroundSrinivasan, G. R., & Brafman, D. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.813544 · Cited by 10 · see citing works
“Prion-like transmission of tau pathology has also been observed in uninjured rodents upon injection of tau oligomers or brain homogenates from rodent models of injury (Gerson et al., 2016; Zanier et al., 2018).”
BackgroundTo, X. V., Soni, N., Medeiros, R., Alateeq, K., & Nasrallah, F. A. (2022) · Brain Research · doi:10.1016/j.brainres.2022.147955 · Cited by 8 · see citing works
The Fate of Tau Aggregates Between Clearance and Transmission
Seitkazina, A., Kim, K. H., Fagan, E., Sung, Y., Kim, Y. K., & Lim, S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.932541 · Cited by 10 · see citing works
Puangmalai, N., Bhatt, N. N., Bittar, A., Jerez, C., Shchankin, N., & Kayed, R. (2023) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2023.102562 · Cited by 17 · see citing works
“…the consistent levels of monomeric tau following BTDP injection emphasize that tau aggregation arises from the intricate interplay between tau conformations and post-translational modifications, as observed in other tau aggregation studies (Gerson et al., 2016; Lasagna-Reeves et al., 2011).”
InfluentialSelf-citationGaikwad, S., Puangmalai, N., Bittar, A., Montalbano, M., Garcia, S., McAllen, S., Bhatt, N., Sengupta, U., & Kayed, R. (2020) · Social Science Research Network · doi:10.2139/ssrn.3753798 · Cited by 5 · see citing works
Self-citationJackson, M., Chen, S., Nguyen, T. T., Siedhoff, H., Balderrama, A., Zuckerman, A., Li, R.-T., Greenlief, C., Cole, G. M., Frautschy, S., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063338 · Cited by 4 · see citing works
“TBI can increase tau oligomers and induce cognitive deficits in human tau Tg mice [26], which can be reversed by administering doxycycline [27].”
BackgroundNovel strategies for targeting tau oligomers in neurodegenerative diseases
Lin, J., Li, H., Jiang, L., & Li, J. (2025) · Journal of Neurology · doi:10.1007/s00415-025-13117-w · Cited by 3 · see citing works
“Synapse loss is one of the earliest hallmarks of AD and tauopathies [85, 86], and studies have shown that tauO can disrupt synaptic function [87, 88], which trigger a range of pathological conditions such as cognitive deficits [89–91].”
Yadikar, H., Johnson, C., Pafundi, N., Nguyen, L. T., Kurup, M., Torres, I., Al-Enezy, A., Yang, Z., Yost, R. A., Kobeissy, F. H., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-022-03165-y · Cited by 5 · see citing works
“In another study, tissue samples from the hippocampus and cerebellum showed elevated tau oligomers, indicating that these oligomers spread pathology post-TBI [19].”
BackgroundVegliante, G., Pischiutta, F., Restelli, E., Moro, F., Chiaravalloti, M. A., Raimondi, I., Bertani, I., Lisi, I., Sammali, E., Pascente, R., et al. (2025) · Annals of Neurology · doi:10.1002/ana.78132 · Cited by 1 · see citing works
“35 Different biomechanical insults may also generate distinct tau oligomeric forms with different toxic potencies, 36 potentially explaining the variable outcomes observed in different brain injuries.”
Miguel, L., Frébourg, T., Campion, D., & Lecourtois, M. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-190906 · Cited by 2 · see citing works
“In mice, tau oligomers have been implicated in synaptic loss [38–40], correlate with memory deficits through synaptic and mitochondrial impairments [38, 41] and potentiate neuronal damage, leading to neurodegeneration following traumatic brain injury [42, 43].”
Sundaresh, S. N., Vogel, E. W., Hue, C. D., Zhang, H., Staniszewski, A., Berman, H. L., Gill, Z., Asam, K. R., Liang, S., Shen, L., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70947 · Cited by 1 · see citing works
Sexually Dimorphic Responses Reveal Multifaceted Benefits of Glibenclamide in Traumatic Brain Injury
Rani, A., Raikwar, S. P., Yoo, W., Ahmad, S., Vagni, V., Janesko‐Feldman, K. L., Carlson, S. W., Eberle, A., Miller, M. E., Helm, J., et al. (2025) · Journal of Neurotrauma · doi:10.1089/neu.2024.0232 · Cited by 1 · see citing works
“49 , 52, 81 – 84 Sex-based Sex-based differences post-TBI post-TBI in cognitive decline remain poorly understood.”
Mitochondrial perturbation drives tau oligomers pathology in Alzheimer’s diseasePreprint
Du, F., Yu, Q., Chen, D., Yan, S. F., & Yan, S. S. (2020) · doi:10.21203/rs.3.rs-40746/v1
Therapeutic target identification, validation and drug discovery for traumatic brain injury
Morin, A. (2020) · doi:10.21954/ou.ro.00010e32 · Cited by 1
“Interestingly, injections of tau oligomers from mTBI (blast or FPI) hTau mice into healthy hTau mice cause cognitive deficits confirming a direct link between the pathologic tau and behavior dysfunction (Gerson et al. 2016).”
BackgroundTraumatic Brain Injury and the Road to Alzheimer’s Disease
Kaveh, R., Kamari, F., Høilund‐Carlsen, P. F., Blaabjerg, M., Christensen, A. A., Poulsen, F. R., Ghaedi, S., Alavi, A. A., & Andalib, S. (2026) · Biomedicines · doi:10.3390/biomedicines14092056
“The increased prevalence of AD years after experiencing TBI appears to involve the post-TBI released tau oligomers, which may seed tau pathology in distant regions from the injury site [153].”
Skrehot, J. T., Matveyenka, M., & Kurouski, D. (2026) · Chemical Communications · doi:10.1039/d6cc02327d
Tau oligomers can occur in human brains within days of a single traumatic brain injuryPreprint
Bhorla, S. K., Steponenaite, A., Allinson, K. S. J., Coleman, M. P., & Vuono, R. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.18.688238
“2 ) ( 11 ).”
Victoroff, J. (2019) · Cambridge University Press eBooks · doi:10.1017/9781139696432.009
Victoroff, J. (2019) · Cambridge University Press eBooks · doi:10.1017/9781139696432.013
TauBI or not TauBI: what was the question?
Sastre, M., Leuven, F. V., & Gentleman, S. (2018) · Brain : a journal of neurology · doi:10.1093/brain/awy225
Pathological Tau as a Cause, and Consequence, of Cellular Dysfunction
Meier, S. E. (2019) · UKnowledge (University of Kentucky) · doi:10.13023/etd.2019.368
“blast injury in wild-type mice, tau oligomerization is increased in the hippocampus at 24 hours post-injury [265] and 72 hours post-injury in the cortex [267].”
BackgroundInfluentialMolecular Aspects of Concussion and Chronic Traumatic Encephalopathy
Farooqui, A. A. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813596-9.00008-0
Radiological Pathological Correlations in Chronic Traumatic Encephalopathy
Gangolli, M. (2018) · doi:10.7936/hpre-aj49
“It is hypothesized that disruption and damage to axons during TBI results in the tau protein to become hyperphosphorylated, first folding as toxic oligomers and later aggregating as neurofibrillary tangles (Gerson et al., 2016; Guzman-Martinez et al., 2013).”
Background
- Authors
- Gerson, J., Castillo-Carranza, D. L., Sengupta, U., Bodani, R., Prough, D. S., DeWitt, D. S., Hawkins, B. E., & Kayed, R.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- University of Texas Medical Branch
- Corresponding author
- Kayed, Rakez
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2016-11
- Volume
- 33
- Issue
- 22
- Pages
- 2034-2043
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- PMC
- PMC5116695
- OpenAlex
- W2337575677
- Cited by
- 94
- References
- 0
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 6 · 2023: 8 · 2022: 11 · 2021: 8 · 2020: 9 · 2019: 11 · 2018: 14 · 2017: 10 · 2016: 5
- FWCI
- 10.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurotrauma (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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
- tau oligomers, traumatic brain injury, cognitive impairment, tauopathy, tau aggregation, blast injury, fluid percussion injury, hippocampus, cerebellum, neurodegeneration, Alzheimer's disease
- MeSH terms
- Brain Injuries, Traumatic, Animals, Hippocampus, Humans, Male, Mice, Transgenic, Stereotaxic Techniques, tau Proteins, Rats, Sprague-Dawley, Mice, Rats, Cognitive Dysfunction
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