Experimental traumatic brain injury induces rapid aggregation and oligomerization of amyloid-beta in an Alzheimer’s disease mouse model
Open accessAbstract
Soluble amyloid-beta (Aβ) oligomers are hypothesized to be the pathogenic species in Alzheimer's disease (AD), and increased levels of oligomers in the brain subsequent to traumatic brain injury (TBI) may exacerbate secondary injury pathways and underlie increased risk of developing AD in later life. To determine whether TBI causes Aβ aggregation and oligomerization in the brain, we exposed triple transgenic AD model mice to controlled cortical impact injury and measured levels of soluble, insoluble, and oligomeric Aβ by enzyme-linked immunosorbent assay (ELISA) at 1, 3, and 7 days postinjury. TBI rapidly increased levels of both soluble and insoluble Aβ40 and Aβ42 in the injured cortex at 1 day postinjury. We confirmed previous findings that identified damaged axons as a major site of Aβ accumulation using both immunohistochemistry and biochemistry. We also report that soluble Aβ oligomers were significantly increased in the injured cortex, as demonstrated by both ELISA and Western blot. Interestingly, the mouse brain is able to rapidly clear trauma-induced Aβ, with both soluble and insoluble Aβ species returning to sham levels by 7 days postinjury. In conclusion, we demonstrate that TBI causes acute accumulation and aggregation of Aβ in the brain, including the formation of low- and high-molecular-weight Aβ oligomers. The formation and aggregation of Aβ into toxic species acutely after injury may play a role in secondary injury cascades after trauma and, chronically, may contribute to increased risk of developing AD in later life.
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Many animal studies show increased production and accumulation of amyloid precursor protein (APP), Aβ, and pathological tau following TBI.
“Second, many animal studies show increased production and accumulation of amyloid precursor protein (APP), Aβ, and pathological tau following TBI (16, 21–28).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [23]
The Results (page not available in our copy) report increased APP processing and Aβ production after TBI in mice, and the Discussion reports increased soluble and insoluble Aβ. The paper does not report increased production or accumulation of APP itself, or a finding about pathological tau; the tau mention found is in a reference title. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCCI TBI increased soluble and insoluble cortical Aβ40 and Aβ42 within 24 h after injury in the 3xTg mouse model of AD, but both soluble and insoluble Aβ returned to sham levels by 7 DPI.
“While CCI TBI increased soluble and insoluble cortical Aβ40 and Aβ42 within 24 h after injury, both soluble and insoluble Aβ returned to sham levels by 7 DPI (23).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [23]
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“[131] An experiment using an AD mouse model involved exposing 3 × Tg AD mice to controlled cortical impact injury and measuring the amount of Aβ accumulation postinjury.[214] TBI rapidly increased the levels of both soluble and insoluble Aβ40 and Aβ42 in the injured cortex.”
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Self-citationA systematic review of large animal models of combined traumatic brain injury and hemorrhagic shock
Mayer, A. R., Dodd, A. B., Vermillion, M. S., Stephenson, D. D., Chaudry, I. H., Bragin, D. E., Gigliotti, A. P., Dodd, R. J., Wasserott, B. C., Shukla, P., et al. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.06.024 · Cited by 23 · see citing works
“Experiments using transgenic rodent models have demonstrated increases in intraaxonal soluble, insoluble and oligomeric Aβ following injury (Washington et al., 2014).”
BackgroundDarkazalli, A., Vied, C., Badger, C.-D., & Levenson, C. W. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2015.4322 · Cited by 19 · see citing works
Martins, A., Zayas‐Santiago, A., Ferrer‐Acosta, Y., Martinez-Jimenez, S. M., Zueva, L. V., Díaz-García, A., & Inyushin, M. Y. (2019) · Biomolecules · doi:10.3390/biom9080350 · Cited by 17 · see citing works
“During this post-traumatic period, the presence of Aβ plaques was also correlated with the presence of soluble Aβ oligomers in the brain [4].”
BackgroundLamprecht, M. R., Elkin, B. S., Kesavabhotla, K., Crary, J., Hammers, J., Huh, J. W., Raghupathi, R., & Morrison, B. (2017) · Journal of Neurotrauma · doi:10.1089/neu.2015.4306 · Cited by 16 · see citing works
Houle, S., & Kokiko‐Cochran, O. N. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.788055 · Cited by 20 · see citing works
Garcia, G. S. P., Gasperi, R. D., Tschiffely, A. E., Sosa, M. A. G., Abutarboush, R., Kawoos, U., Statz, J. K., Ciarlone, S. L., Reed, E., Jeyarajah, T., et al. (2021) · Journal of Neurotrauma · doi:10.1089/neu.2021.0184 · Cited by 16 · see citing works
Mohamed, L. W., Abuel-Maaty, S. M., Mohammed, W. A., & Galal, M. (2018) · Bioorganic chemistry (Print) · doi:10.1016/j.bioorg.2017.11.008 · Cited by 14
“The fifteen new compounds IIa-c, IIIa-h, V, VI and IX were subjected to pharmacological screening and were tested for their acetyl cholinesterase inhibitory activity and b amyloid protein content against donepezil as reference in vivo, following reported procedure [16,17].”
MethodIyappan, A., Kawalia, S. B., Raschka, T., Hofmann-Apitius, M., & Senger, P. (2016) · Journal of Biomedical Semantics · doi:10.1186/s13326-016-0079-8 · Cited by 13 · see citing works
“However, increased BACE1 activity has been reported to be associated with amyloid-beta aggregation in AD patients [105].”
BackgroundWashington, P. M., & Burns, M. P. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw049 · Cited by 11 · see citing works
“We do not believe this to be the case because we have previously shown that TBI-induced changes in Ab42 follow an identical time course to that of Ab40 in C57Bl/6 mice (41) and APP transgenic mice (39).”
ResultSelf-citationCorrigan, F., Arulsamy, A., Teng, J., & Collins‐Praino, L. E. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2016.4589 · Cited by 20 · see citing works
“92,118 This may subsequently lead to an upregulation of A b expression, 116,119 particularly of A b 42, 90 over time, which may set into motion the pathogenic amyloid cascade seen in AD.”
NeuroTransDB: highly curated and structured transcriptomic metadata for neurodegenerative diseases
Bagewadi, S., Adhikari, S., Dhrangadhariya, A., Irin, A. K., Ebeling, C., Namasivayam, A. A., Page, M., Hofmann‐Apitius, M., & Senger, P. (2015) · Database · doi:10.1093/database/bav099 · Cited by 14 · see citing works
Pybus, A. F., Bitarafan, S., Brothers, R. O., Rohrer, A., Khaitan, A., Moctezuma, F. R., Udeshi, K., Davies, B., Triplett, S., Griffin, M. N., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03128-1 · Cited by 12 · see citing works
Zedde, M., Piazza, F., & Pascarella, R. (2025) · Biomedicines · doi:10.3390/biomedicines13040881 · Cited by 12 · see citing works
“Additionally, experimental models in swine [3,62–64] and mice [64] confirm that injured axons serve as focal points of A β production after trauma.”
Rogers, E. A., Beauclair, T., Martinez, J., Mufti, S. J., Kim, D., Sun, S., Stingel, R. L., Dieterly, A. M., Krishnan, N., Crodian, J. S., et al. (2023) · Lab on a Chip · doi:10.1039/d3lc00248a · Cited by 13 · see citing works
Ubukata, S., Oishi, N., Higashi, T., Kagawa, S., Yamauchi, H., Okuyama, C., Watanabe, H., Ono, M., Saji, H., Aso, T., et al. (2020) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s268504 · Cited by 9 · see citing works
Amyloid-β and tau deposition in traumatic brain injury: a study of Vietnam War veterans
de Bruin, H., Groot, C., Kamps, S., Vijverberg, E. G. B., Steward, A., Dehsarvi, A., Pijnenburg, Y. A. L., Ossenkoppele, R., & Franzmeier, N. (2024) · Brain Communications · doi:10.1093/braincomms/fcaf009 · Cited by 5 · see citing works
“Interestingly, animal models have shown that mice exposed to TBI generally accumulated A β and tau close to the area of injury, 35-37 and in one specific study, the authors showed that p-tau spread from this initial site of injury to synaptically connected regions.”
Frackowiak, J., & Mazur‐Kolecka, B. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1160967 · Cited by 7 · see citing works
“Aβ accumulated mainly in damaged axons, and the levels of soluble low-and high-molecular-weight Aβ oligomers were significantly increased in the injured cortex during a week after the insult (Washington et al., 2014).”
BackgroundMahmoud, Z., Mohamed, L. W., Mohamed, K. O., Sayed, H. S., Fattah, M. A. A. E., & El-Malah, A. A. (2023) · Medicinal Chemistry Research · doi:10.1007/s00044-022-03013-7 · Cited by 6 · see citing works
Maigler, K. C., Buhr, T. J., Park, C. S., Miller, S. A., Kozlowski, D. A., & Marr, R. A. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2020.6989 · Cited by 8 · see citing works
Gharahi, H., Garimella, H. T., Chen, Z., Gupta, R. K., & Przekwas, A. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1007062 · Cited by 5 · see citing works
“Repeated concussions, relatively common in contact sports, have been recognized as serious medical events that can cause sustained cognitive and psychiatric changes, as well as neurodegeneration (McKee et al., 2009; Prins et al., 2013; Greco et al., 2019; Zetterberg et al., 2019; Kashyap et al., 2022).”
BackgroundImmune signaling and function in neurodegeneration
Latour, Y. L., & McGavern, D. B. (2026) · Journal of Clinical Investigation · doi:10.1172/jci199850 · Cited by 7 · see citing works
“…acute and chronic proteinopathy, including elevations in total and oligomeric tau (201), transient increases in soluble and insoluble A β species (202), enhanced hippocampal A β deposition at later time points (203, 204), and broader neurodegenerative protein signatures following repetitive…”
Sudha, H. G., Muthukumarasamy, A., Ramaraj, D., Kunjiappan, S., Pandian, G. N., Chockalingam, S., & Packirisamy, G. (2026) · Industrial Crops and Products · doi:10.1016/j.indcrop.2025.122600 · Cited by 4 · see citing works
Bamel, K., Panwar, A., Kumar, M., Kumar, S., Sharma, V., & Sharma, A. K. (2025) · Brain Disorders · doi:10.1016/j.dscb.2025.100232 · Cited by 5 · see citing works
Traumatic Brain Injury: Role in Induction and Progression of Neurodegenerative Disorders
Kumar, S., Sharma, P., Kumar, D., Gulia, S., Rajni, R., & Thakur, M. (2024) · Research Journal of Pharmacy and Technology · doi:10.52711/0974-360x.2024.00303 · Cited by 7 · see citing works
Patta, P. C., de Oliveira, E. M. N., Goulart, A. C. F., Zaluski, A. B., Papaléo, R. M., & Vianna, M. R. M. R. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.02.031 · Cited by 4 · see citing works
Murine Non-Transgenic Models of Alzheimer’s Disease Pathology: Focus on Risk Factors
Rodríguez, M. H., López, J. M. V., Rosas, M., Nicolás‐Vázquez, M. I., & Jiménez, E. M. (2025) · Brain Sciences · doi:10.3390/brainsci15030322 · Cited by 2 · see citing works
Wellman, S. M., Coyne, O., Douglas, M. M., & Kozai, T. D. Y. (2023) · Journal of Neural Engineering · doi:10.1088/1741-2552/aceca5 · Cited by 8 · see citing works
“Alternatively, brain injury is known to increase the rate of APP processing, production of amyloid/tau, and aggregation of plaques [51, 52] and microglia naturally phagocytose and sequester amyloid for proper degradation and removal from the brain [48].”
Ojo, J. O., Leary, P., Lungmus, C., Algamal, M., Mouzon, B., Bachmeier, C. J., MULLAN, M. J., Stewart, W. B., Jr., & Crawford, F. (2018) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nly101 · Cited by 3 · see citing works
McLeod, R. E., Kale, K. M., Weglinski, C., Masoud, A. M., Akbar, N., Probert, F., Anthony, D. C., & Zainal, J. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.07.027 · Cited by 2 · see citing works
Wellman, S., Coyne, O. A., Douglas, M. M., & Kozai, T. (2023) · bioRxiv · doi:10.1101/2023.02.11.528131 · Cited by 2 · see citing works
Traumatic Injury Reduces Amyloid Plaque Burden in the Transgenic 5xFAD Alzheimer’s Mouse Spinal Cord
Chu, T., Cummins, K., & Stys, P. K. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200387 · Cited by 2 · see citing works
“In transgenic mice overexpressing human APP and/or presenilin gene mutations, most injury studies found an acute increase of amyloid-(cid:2) peptide as measured by western blot or ELISA [15, 16].”
Hiraoka, T. (2019) · Neurocase · doi:10.1080/13554794.2019.1599026 · Cited by 3 · see citing works
Yue, J., Carriquiriborde, V., Cheng, W. H., Yildirim, T., Fan, J., Tok, S., Kelly, M., Wellington, C. L., & Kent, B. A. (2026) · Journal of Neurotrauma · doi:10.1177/08977151261430301 · Cited by 2 · see citing works
“93 – 95 However, how rmTBI alters protein aggregation in mice remains unclear.”
Xie, Z., Li, T., Su, W. C., Lou, Y., Zhang, Y., Zhou, X., Li, Z., Bai, X., & Liu, X. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14402 · Cited by 1 · see citing works
“6,7 The accumulation of amyloid plaques is a common pathological feature observed in both TBI and AD patients.”
BackgroundProfiling the neuroimmune cascade in 3xTg mice exposed to successive mild traumatic brain injuriesPreprint
Pybus, A., Bitarafan, S., Brothers, R., Rohrer, A., Khaitan, A., Moctezuma, F. R., Udeshi, K., Davies, B., Triplett, S. E., Dammer, E., et al. (2023) · bioRxiv · doi:10.1101/2023.06.13.544838 · Cited by 1 · see citing works
“This model is widely used to study AD and is increasingly utilized in brain injury research (42–49).”
BackgroundMethodChronic traumatic encephalopathy: the nature, mechanisms and stages of development
Eg, P., & Лисяный, Н. И. (2019) · Ukrainian Neurosurgical Journal · doi:10.25305/unj.168890
Traumatic 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
“Furthermore, an experimental study on triple transgenic AD mice reported rapid increases in soluble and insoluble A β forms in the injured cortex, with injured axons identified as a major site of accumulation [148].”
Poffenberger, C. N., Taylor, M., Larson, K., Mufson, E., & Dixon, K. (2026) · Journal of Neurotrauma · doi:10.1177/08977151261469044
A Molecular Mechanism of Stress-Induced Alzheimer’s Disease; Part 1
Chapman, M. R., Zhou, W., & Yeh, G. S. Y. (2023) · Journal of Macromolecular Science Part B · doi:10.1080/00222348.2023.2228588
“[43,44] Athletes have been found to have greater susceptibility to AD because of ).”
Development of carbon dots to manage Alzheimer's disease and Parkinson's disease
Kuo, Y.-C., & De, S. (2023) · Journal of the Taiwan Institute of Chemical Engineers / Elsevier · doi:10.1016/j.jtice.2023.104799
RetractedWhat Happens to Concussed Animals?
Victoroff, J. (2019) · Cambridge University Press eBooks · doi:10.1017/9781139696432.006
Recombinant Antibodies as Reagents
Johnson, M. (2015) · Materials and Methods · doi:10.13070/mm.en.5.1297
Structural and functional imaging of tauopathies
Smith‐Forrester, J. (2015) · cIRcle (University of British Columbia) · doi:10.14288/1.0166402
- Authors
- Washington, P. M., Morffy, N., Parsadanian, M., Zapple, D. N., & Burns, M. P.
- Affiliations
- Georgetown University Medical Center (US)
- Corresponding author
- Burns, Mark P.
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2014-01
- Volume
- 31
- Issue
- 1
- Pages
- 125-134
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- PMC
- PMC3919479
- OpenAlex
- W2055079309
- Cited by
- 103
- References
- 61
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 6 · 2023: 11 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 11 · 2018: 8 · 2017: 11 · 2016: 13 · 2015: 9 · 2014: 4
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurotrauma (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Georgetown University (T32NS041218)
- Cosmos Club Foundation
- National Institute of Neurological Disorders and Stroke (R03NS067417, R01NS081068, T32NS041218)
- 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, amyloid-beta, amyloid-beta oligomers, Alzheimer's disease, controlled cortical impact, triple transgenic mouse model, axonal injury, amyloid-beta clearance, secondary injury, cortical injury
- MeSH terms
- Alzheimer Disease, Animals, Brain, Brain Injuries, Disease Models, Animal, Mice, Transgenic, Amyloid beta-Peptides, Mice
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