Does neuroinflammation drive the relationship between tau hyperphosphorylation and dementia development following traumatic brain injury?
Abstract
A history of traumatic brain injury (TBI) is linked to an increased risk for the later development of dementia. This encompasses a variety of neurodegenerative diseases including Alzheimer's Disease (AD) and chronic traumatic encephalopathy (CTE), with AD linked to history of moderate-severe TBI and CTE to a history of repeated concussion. Of note, both AD and CTE are characterized by the abnormal accumulation of hyperphosphorylated tau aggregates, which are thought to play an important role in the development of neurodegeneration. Hyperphosphorylation of tau leads to destabilization of microtubules, interrupting axonal transport, whilst tau aggregates are associated with synaptic dysfunction. The exact mechanisms via which TBI may promote the later tauopathy and its role in the later development of dementia are yet to be fully determined. Following TBI, it is proposed that axonal injury may provide the initial perturbation of tau, by promoting its dissociation from microtubules, facilitating its phosphorylation and aggregation. Altered tau dynamics may then be exacerbated by the chronic persistent inflammatory response that has been shown to persist for decades following the initial impact. Importantly, immune activation has been shown to play a role in accelerating disease progression in other tauopathies, with pro-inflammatory cytokines, like IL-1β, shown to activate kinases that promote tau hyperphosphorylation. Thus, targeting the inflammatory response in the sub-acute p…
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Chronic neuroinflammation could provoke tau pathology thereby worsening neuronal injury and long-term outcome.
“Together, these studies indicate that chronic neuroinflammation could provoke tau pathology thereby worsening neuronal injury and long-term outcome.”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [149]
A robust and persistent neuroinflammatory response may be sufficient to promote phosphorylation, aggregation, and subsequent neurodegeneration; key features of AD.
“A robust and persistent neuroinflammatory response may then be sufficient to promote phosphorylation, aggregation, and subsequent neurodegeneration; key features of AD (149–151).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [149]
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Tan, X. L., Zheng, P., Wright, D. K., Sun, M., Brady, R. D., Liu, S., McDonald, S. J., Mychasiuk, R., Cenap, S., Jones, N. C., et al. (2019) · Brain Injury · doi:10.1080/02699052.2019.1667539 · Cited by 16 · see citing works
“For example, neuroinflammation is another common secondary injury in TBI and has been linked to tau abnormalities in TBI and related conditions (35).”
BackgroundLiu, S., Wang, M., Haiyan, X., Ye, J., Cao, L., Li, W., & Sun, G. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e28581 · Cited by 16 · see citing works
Laudanski, K., Hajj, J., Restrepo, M., Siddiq, K., Okeke, T. K., & Rader, D. (2021) · Biomedicines · doi:10.3390/biomedicines9121791 · Cited by 15 · see citing works
Nakhjiri, E., Vafaee, M. S., Hojjati, S. M. M., Shahabi, P., & Shahpasand, K. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02061-7 · Cited by 14 · see citing works
Halicki, M. J., Hind, K., & Chazot, P. L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612556 · Cited by 18 · see citing works
Sex-Differences in Traumatic Brain Injury in the Absence of Tau in Drosophila
Shah, E. J., Gurdziel, K., & Ruden, D. M. (2021) · Genes · doi:10.3390/genes12060917 · Cited by 6 · see citing works
Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease
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Neuroprotective and neuroregenerative drugs after severe traumatic brain injury
Grgac, I., Herzer, G., Voelckel, W. G., Secades, J., & Trimmel, H. (2024) · Wiener Klinische Wochenschrift · doi:10.1007/s00508-024-02367-9 · Cited by 13 · see citing works
Mollayeva, T., Pacheco, N., D'Souza, A., & Colantonio, A. (2017) · BMJ Open · doi:10.1136/bmjopen-2017-017165 · Cited by 13 · see citing works
Satellite microglia: marker of traumatic brain injury and regulator of neuronal excitability
Feichtenbiner, A., Sytsma, K., O’Boyle, R. P., Mittenzwei, R., Maioli, H., Scherpelz, K. P., Child, D. D., Li, N., Ariza, J., Keene, L. M., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03328-9 · Cited by 11 · see citing works
““Neuroinflammation” or reactive gliosis also occurs alongside injury and may contribute to progressive pathology after TBI [12], with astrocytes and microglia thought to produce inflammatory cytokines, inappro-priately phagocytize synapses and/or contribute to cell death [13–17].”
Spatiotemporal profile of atrophy in the first year following moderate‐severe traumatic brain injury
Brennan, D. J., Duda, J., Ware, J., Whyte, J., Choi, J., Gugger, J. J., Focht, K., Walter, A., Bushnik, T., Gee, J., et al. (2023) · Human Brain Mapping · doi:10.1002/hbm.26410 · Cited by 10 · see citing works
“Tau changes in disease sites are also known to follow acute axonal injury (Collins-Praino & Corrigan, 2017), and axonal microstructural disruption has been identified in white matter underlying sulci with high levels of tau pathology (Holleran et al., 2017).”
BackgroundAn exhaustive analysis of post-traumatic brain injury dementia using bibliometric methodologies
Sang, X., Wang, C.-Q., Chen, W., Rong, H., & Hou, L.-J. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1165059 · Cited by 10 · see citing works
Shah, E. J., Hüttemann, M., Sanderson, T. H., Gurdziel, K., & Ruden, D. M. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.628777 · Cited by 14 · see citing works
Schneider, L. E., Reichert, E. C., Faulkner, J., Reichert, B., Sonnen, J. A., & Hawryluk, G. W. J. (2019) · Journal of neurosurgery · doi:10.3171/2018.10.jns181517 · Cited by 10 · see citing works
Katramadou, A., Bender, E. S., & Kanakis, D. N. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27031570 · Cited by 9 · see citing works
“Activated microglia release pro-inflammatory cytokines, namely IL-1 β , IL-6, and tumor necrosis factor (TNF)- α , which exacerbate tau hyperphosphorylation through kinase-dependent cascades [217].”
Kaniuk, J. K., Kumar, D., Mazurek, C. Y., Khavari, S., Sollenberger, C. H., Ahuja, A., Mossner, J. M., & Ahuja, C. S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157191 · Cited by 11 · see citing works
“Since IL-1 β levels can remain elevated for over a decade post-injury, this offers a potential explanation for chronic microtubule dysfunction in TBI [81].”
Alipour, M., Tebianian, M., Tofigh, N., Taheri, R. S., Mousavi, S. A., Naseri, A., Ahmadi, A., Munawar, N., & Shahpasand, K. (2022) · Neuropeptides · doi:10.1016/j.npep.2022.102285 · Cited by 9 · see citing works
Srinivasan, G. R., & Brafman, D. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.813544 · Cited by 10 · see citing works
“On the other hand, the effect of a single TBI on tau pathology is yet to be understood (Collins-Praino and Corrigan, 2017).”
BackgroundSpinal Cord Injury Causes Prominent Tau Pathology Associated with Brain Post-Injury Sequela
Nakhjiri, E., Roqanian, S., Zangbar, H. S., Vafaee, M. S., Mohammadnejad, D., Ahmadian, S., Zamanzadeh, S., Ehsani, E., Shahabi, P., & Shahpasand, K. (2021) · Molecular Neurobiology · doi:10.1007/s12035-022-02843-1 · Cited by 8 · see citing works
“SCI can disrupt nerve impulse conduction, resulting in neurological dysfunction [4].”
BackgroundLiu, X., Mao, S., Yuan, Y., Wang, Z.-L., Tian, Y., Tao, L., & Dai, J.-H. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1517087 · Cited by 7 · see citing works
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Soni, 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
“The role of neuroinflammation in tau pathogenesis has also been extensively documented (Curran and O’Connor, 2001; Sutinen et al., 2012; Morales et al., 2013; Collins-Praino and Corrigan, 2017; Leyns and Holtzman, 2017; Laurent et al., 2018).”
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“Along with these changes, the accumulated tau protein stimulates neuroinflammation via inhibition of the transportation of APP vesicles, neurofilaments, and even organelles, and the production of ROS [136–139].”
Kleven, B. D. C., Chien, L., Cross, C., Labus, B., & Bernick, C. (2025) · The journal of head trauma rehabilitation · doi:10.1097/htr.0000000000001048 · Cited by 4 · see citing works
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Early cerebrospinal fluid elevations of pTau-217 in severe traumatic brain injury subjects
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Zhang, Z.-X., Gao, J., Li, G., Cheng, J.-E., Yu, J.-T., Wang, P.-C., Liu, R.-N., Jiang, C., Ma, H.-L., & Zhao, Y. (2025) · BMC Neurology · doi:10.1186/s12883-025-04303-4 · Cited by 2 · see citing works
“Tau phosphorylation has been widely explored and is considered an important factor in neurodegenerative diseases after TBI, though the relevance needs to be further confirmed [9, 10].”
Mavroudis, I. A., Petridis, F., Ciobica, A. S., Kamal, F. Z., Pădurariu, M., & Kazis, D. A. (2025) · Acta Neurologica Belgica · doi:10.1007/s13760-024-02695-7 · Cited by 3 · see citing works
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Traumatic brain injury (TBI) and mortality in older adults with and without pre-injury dementiaPreprint
Lai, H., Soreq, E., Bourke, N. J., Baker, C., Zimmerman, K., Parkinson, M., Daniels, S., Gregg, E. W., Sharp, D., & Li, L.-M. (2024) · medRxiv · doi:10.1101/2024.10.09.24314691 · Cited by 1 · see citing works
“Pre-injury dementia may also increase risk of poor outcomes post-TBI as neurodegenerative processes, such as neuroinflammation, may exacerbate secondary injury effects of TBI 20,21 , while cognitive disturbances may interfere with rehabilitation and subsequent functional recovery.”
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A 3D Human Neuron‐on‐Chip Platform to Monitor Neuronal Injury Responses
Tang, R., Latchoumane, C.-F. V., Chopra, A., Sarkar, M. M., Kim, C., Gonsalves, N., Wu, H., Sentmanat, J. C., Liu, A., Mhatre‐Winters, I., et al. (2026) · Advanced Healthcare Materials · doi:10.1002/adhm.202503457
Post-traumatic dementia: Advances in understanding neurodegenerative mechanisms
He, X.-J., Wang, H., & Zhang, Y. (2026) · Chinese Medical Sciences Journal · doi:10.1016/j.cmsj.2026.08.001
Neuroprotektive und -regenerative Medikation nach schwerem Schädel-Hirn-Trauma
Trimmel, H., Grgač, I., Herzer, G., & Matula, C. (2024) · Anästhesie Nachrichten · doi:10.1007/s44179-024-00264-0
Chronic Traumatic Encephalopathy: A Literature Review
Johnson, Y. M., Mballa, C. E., Mewhiney, T. S., Nkabyo, C.-A. Z., & Tieko, G. L. (2021) · Scholarly Research In Progress · doi:10.64057/001c.142415
“An additional study confirmed a correlation between these diseases' neuropathologic processes through postmortem analyses, which demonstrated white matter with oligodendrogenesis in both CTE and Alzheimer's disease patients (82).”
Sustained Tau Phosphorylation and Microglial Activation Following Repetitive Traumatic Brain Injury
Siahaan, A. M. P., Indharty, R. S., Chrestella, J., Sadewo, W., Tandean, S., & Syarifah, S. (2020) · Open Access Macedonian Journal of Medical Sciences · doi:10.3889/oamjms.2020.5471
“The mechanism mediating TBI-induced phosphorylation and aggregation of tau protein is still uncertain, but microglial activation and ensuing neuroinflammation are strongly implicated [15], [16].”
Victoroff, J. (2019) · Cambridge University Press eBooks · doi:10.1017/9781139696432.013
- Authors
- Collins-Praino, L. E., & Corrigan, F.
- Affiliations
- Adelaide University (AU)
- Corresponding author
- Corrigan, Frances
- ORCID
- Corrigan, Frances
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 60
- Pages
- 369-382
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W2526775532
- Cited by
- 95
- References
- 0
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 10 · 2023: 11 · 2022: 13 · 2021: 12 · 2020: 7 · 2019: 11 · 2018: 7 · 2017: 10
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- Neurosurgical Research Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- traumatic brain injury, neuroinflammation, tau hyperphosphorylation, dementia, Alzheimer's disease, chronic traumatic encephalopathy, tauopathy, axonal injury, microtubule destabilization, inflammatory cytokines, IL-1β, immune activation, neurodegeneration
- MeSH terms
- Brain Injuries, Traumatic, Alzheimer Disease, Animals, Axons, Dementia, Humans, Inflammation, Phosphorylation, tau Proteins, Tauopathies
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