Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model
Abstract
Traumatic brain injury (TBI) is a risk factors for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in dementia pugilistica (DP), a syndrome characterized by progressive dementia, parkinsonism, and the hallmark brain lesions of AD, including neurofibrillary tangles (NFTs), formed by abnormal tau filaments and senile plaques (SPs) composed of Abeta fibrils. Previous study showed that mild rTBI (mrTBI) accelerated the deposition of Abeta in the brains of transgenic (Tg) mice (Tg2576) that over-express human Abeta precursor proteins with the familial AD Swedish mutations (APP695swe) and model of AD-like amyloidosis. Here, we report studies of the effects of mrTBI on AD-like tau pathologies in Tg mice expressing the shortest human tau isoform (T44) subjected to mrTBI, causing brain concussion without structural brain damage to simulate injuries linked to DP. Twelve-month-old Tg T44 (n = 18) and wild-type (WT; n = 24) mice were subjected to mrTBI (four times a day, 1 day per week, for 4 weeks; n = 24) or sham treatment (n = 18). Histopathological analysis of mice at 9 months after mrTBI revealed that one of the Tg T44 mice showed extensive telencephalic NFT and cerebral atrophy. Although statistical analysis of neurobehavioral tests at 6 months after mrTBI did not show any significant difference in any of groups of mice, the Tg T44 mouse with extensive NFT had an exceptionally low neurobehavioral score. The reasons for the augmentation of tau pathologies in only o…
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Only transgenic tau mouse models [T44 (one mouse), hTau] displayed NFT pathology following repetitive TBI.
“Similarly, only transgenic tau mouse models [T44 (one mouse), hTau] displayed NFT pathology following repetitive TBI (153, 234).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [234]
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MethodClinical correlates in an experimental model of repetitive mild brain injury
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Farfel, J. M., Yu, L., Jager, P. L. D., Schneider, J. A., & Bennett, D. A. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.09.011 · Cited by 135 · see citing works
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ResultAmyloid-beta and tau pathology following repetitive mild traumatic brain injury
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Animal models of traumatic brain injury
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“, scalp reflected, no craniotomy), the CCI model has been used to deliver 2–3 impacts over 1–2 days (Laurer et al. 2001; Uryu et al. 2002; Conte et al. 2004; Longhi et al. 2005; Yoshiyama et al. 2005; Shitaka et al. 2011; Bennett et al. 2012; Mouzon et al. 2012).”
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“Tau mutations (Klein et al., 2004) and chronic traumatic encephalopathy (Baugh et al., 2012; Yoshiyama et al., 2005) are but two of the potential etiologies that require further investigation.”
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Neuroradiological Changes Following Single or Repetitive Mild TBI
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“This was consistent with several human and animal studies that showed that repetitive injury separated by short intervals poses a greater risk than single insults or multiple head injuries separated by longer intervals (Laurer et al., 2001; Yoshiyama et al., 2005; Meehan et al., 2012; Prins et al., 2013; Silverberg et…”
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Models of Mild Traumatic Brain Injury
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Kinetics of human mutant tau prion formation in the brains of 2 transgenic mouse lines
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Brain Injury in the Context of Tauopathies
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“For instance, CCI does not induce tau pathology in wild-type mice, and it only does so in transgenic models where wild type or mutant tau (P301L) is expressed [24, 25, 200].”
BackgroundModelling human pathology of traumatic brain injury in animal models
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“Reference (79–81) (79–82) (83–91) (92–97) (83, 90, 98, 99) (77, 78, 100) (75–106)”
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“A commonly used test for cognition in rodents is the Morris water maze (MWM), which specifically evaluates spatial learning and memory [for a detailed description, see Ref.”
BackgroundInfluentialAnimal Models of Traumatically-Induced Dementia
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Does Traumatic Brain Injury Hold the Key to the Alzheimer’s Puzzle?
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“For instance, our TBI model provides accelerated development of neurodegenerative brain pathologies and neuronal compromise and death and can supplement or possibly replace existing models for drug interventions against AD and perhaps other neurodegenerative diseases, as supported by others [33,84,85].”
BackgroundMechanical stress models of Alzheimer's disease pathology
Levy-Nogueira, M., Epelbaum, S., Steyaert, J.-M., Dubois, B., & Schwartz, L. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2015.10.005 · Cited by 33 · see citing works
“Unlike humans with AD, transgenic mouse models based on Ab accumulation do not develop NFTs, yet many do show increased tau hyperphosphorylation [94] (Table 1).”
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“53 54–69 Recent promising studies already detected important roles for inflammatory processes 55,64,65 and cis -phosphorylated tau 62,66–68,70 In order to expand our knowledge about the chronic sequelae of TBI, the current study was therefore not only designed to evaluate histopathological…”
Garcia, G. S. P., Perez, G. M., Gasperi, R. D., Sosa, M. G., Otero-Pagan, A., Pryor, D., Abutarboush, R., Kawoos, U., Hof, P., Cook, D., et al. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2020.7398 · Cited by 30 · see citing works
The Impact of Traumatic Brain Injury on the Aging Brain
Young, J. S., Hobbs, J. G., & Bailes, J. E. (2016) · Current Psychiatry Reports · doi:10.1007/s11920-016-0719-9 · Cited by 34 · see citing works
Traumatic brain injury and the pathways to cerebral tau accumulation
Flavin, W. P., Hosseini, H. C., Ruberti, J. W., Kavehpour, H. P., Giza, C. C., & Prins, M. L. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1239653 · Cited by 30 · see citing works
“RmTBI in a TgT44 mouse model only found 1 animal with neurofibrillary tangles 9 months after injury (125).”
BackgroundLi, M., Reisman, J. I., Morris-Eppolito, B., Qian, S. X., Kazis, L. E., Wolozin, B. L., Goldstein, L. E., & Xia, W. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00589-3 · Cited by 26 · see citing works
Thomsen, G. M., Ma, A. M., Ko, A., Harada, M. Y., Wyss, L. S., Haro, P. S., Vit, J., Shelest, O., Rhee, P., Svendsen, C. N., et al. (2016) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0000000000001248 · Cited by 29 · see citing works
“Injury intervals were designed to allow for recovery from the acute symptoms of mild TBI between injury events and are similar to previously reported repetitive injury models.(13)”
BackgroundResultSweeney, N., Kim, T. Y., Morrison, C. T., Li, L., Acosta, D. M., Liang, J., Datla, N. V., Fitzgerald, J. A., Huang, H., Liu, X., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02810-1 · Cited by 27 · see citing works
“Previous reports indicate that TBI increases tau pathology in several mouse models [23, 27, 44, 45, 66, 74, 91, 97, 107, 112].”
BackgroundGangolli, M., Benetatos, J., Esparza, T. J., Fountain, E. M., Seneviratne, S., & Brody, D. L. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2018.5700 · Cited by 27 · see citing works
“12 More recent work found that while repetitive closed headed impacts caused progressive behavioral impairments and neuroinflammation, there was no ptau pathology at chronic time-points up to 6 and 12 months post-injury using immunohistochemistry methods.”
Drug abuse, brain calcification and glutamate-induced neurodegeneration.
Rodríguez, M. J., Pugliese, M., & Mahy, N. (2009) · Current Drug Abuse Reviews · doi:10.2174/1874473710902010099 · Cited by 27 · see citing works
“Acute neurological injury and chronic brain damage has been related in boxing participants, with a correlation in the prevalence of subdural hematoma and dementia pugilistica [127;128].”
BackgroundMechanical stress increases brain amyloid β, tau, and α‐synuclein concentrations in wild‐type mice
Levy-Nogueira, M., Hamraz, M., Abolhassani, M., Bigan, E., Lafitte, O., Steyaert, J.-M., Dubois, B., & Schwartz, L. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2017.11.003 · Cited by 26 · see citing works
“Unlike our results, one study using wild-type mice subjected to rmTBI (4!/day, 1 day/week for 4 weeks) did not reproduce postinjury tau changes [11].”
BackgroundResultModeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery
Turner, R. C., Lucke-Wold, B. P., Logsdon, A. F., Robson, M. J., Lee, J. M., Bailes, J. E., Dashnaw, M. L., Huber, J. D., Petraglia, A. L., & Rosen, C. L. (2015) · Frontiers in Neurology · doi:10.3389/fneur.2015.00223 · Cited by 23 · see citing works
“The affected mouse displayed neuropathological changes that included heightened tau burden, the presence of NFTs, and cognitive deficits (35).”
BackgroundInfluentialChronic Traumatic Encephalopathy: A Critical Appraisal
Levin, B., & Bhardwaj, A. (2013) · Neurocritical Care · doi:10.1007/s12028-013-9931-1 · Cited by 22 · see citing works
“The mouse that developed cognitive impairment had increased iron deposits in the ventral cortical regions which may have increased NFT deposition leading to the speculation that perivascular hemorrhages found in boxers may lead to a similar process [20].”
BackgroundA High-Throughput Screening Assay for Determining Cellular Levels of Total Tau Protein
Dehdashti, S., Zheng, W., Gever, J. R., Wilhelm, R. S., Nguyễn, Ð.-T., Sittampalam, G. S., McKew, J. C., Austin, C. P., & Prusiner, S. B. (2013) · Current Alzheimer Research · doi:10.2174/15672050113109990143 · Cited by 23 · see citing works
“frontotemporal dementias (FTDs), traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP) and Niemann-Pick type C (NPC) (1, 2).”
BackgroundJuan, S. M. A., Daglas, M., & Adlard, P. A. (2022) · Journal of Neurotrauma · doi:10.1089/neu.2021.0241 · Cited by 21 · see citing works
Cytoskeletal protein α-II spectrin degradation in the brain of repeated blast exposed mice.
Valiyaveettil, M., Alamneh, Y., Wang, Y., Arun, P., Oguntayo, S., Wei, Y., Long, J., & Nambiar, M. (2014) · Brain Research · doi:10.1016/j.brainres.2013.12.031 · Cited by 21 · see citing works
Albayram, Ö., MacIver, B., Mathai, J., Verstegen, A. M. J., Baxley, S., Qiu, C., Bell, C. A., Caldarone, B. J., Zhou, X. Z., Lu, K. P., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-45234-8 · Cited by 24 · see citing works
The hidden variables problem in Alzheimer's disease clinical trial design
Liyanage, S., Santos, C., & Weaver, D. F. (2018) · Alzheimer's & Dementia · doi:10.1016/j.trci.2018.09.003 · Cited by 20 · see citing works
“In Tg2576 murine models, repeated brain injuries were directly associated with a significant increase in neurofibrillary tangles, cerebral atrophy, and cognitive deficits [21].”
BackgroundCai, X., Harding, I. C., Sadaka, A. H., Colarusso, B. A., Kulkarni, P., Ebong, E. E., Qiao, J., O'Hare, N. R., & Ferris, C. F. (2021) · Brain Communications · doi:10.1093/braincomms/fcab265 · Cited by 22 · see citing works
Bai, Y., & Ma, X. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106790 · Cited by 21 · see citing works
Leśniak, A., Leszczyński, P., Bujalska‐Zadrożny, M., Pick, C. G., & Sacharczuk, M. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.03.015 · Cited by 20 · see citing works
The utility of clinical criteria in patients with chronic traumatic encephalopathy
Laffey, M., Darby, A., Cline, M. G., Teng, E., & Mendez, M. (2018) · NeuroRehabilitation (Reading, MA) · doi:10.3233/nre-182452 · Cited by 18 · see citing works
“…Stewart, & Smith, 2012; Lakis, Corona, Toshkezi, & Chin, 2013; McCrory, Meeuwisse, Kutcher, Jordan, & Gardner, 2013; McKee et al., 2009; McKee et al., 2013; Schmidt, Zhukareva, Newell, Lee, & Trojanowski, 2001; Smith, Johnson, & Stewart, 2013; Sponheim et al., 2011; Yoshiyama et al., 2005).”
Tau overexpression exacerbates neuropathology after repeated mild head impacts in male mice
Cheng, H., Deaton, L. M., Qiu, M., Ha, S., Pacoma, R., Lao, J., Tolley, V., Moran, R., Keeton, A., Lamb, J. R., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104683 · Cited by 16 · see citing works
“In the literature, there is inconsistency for rmTBI to induce tauopathy in rodents, especially in a C57BL/6 background [62-66].”
Literature-Related Discovery (LRD)
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Quantitative Imaging of Blood-Brain Barrier Permeability Following Repetitive Mild Head Impacts
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“Unlike contusion TBI, the formation of tau misfolded aggregates may take a longer time to develop after rCHI which exhibits a distinct immune response from the one that accompanies CCI and cerebral contusion [24,52].”
BackgroundRodríguez, M. J., Prats, A., Malpesa, Y., Andrés, N., Pugliese, M., Batlle, M., & Mahy, N. (2009) · Journal of Neurotrauma · doi:10.1089/neu.2008.0553 · Cited by 13
“Previous studies done with quisqualic or ibotenic acid under similar conditions, found a similarly severe atrophy of the medial septum after a 1-year period (Ramani et al., 2006; Yoshiyama et al., 2005; Leutgeb and Mizumori, 1999; Mahy et al., 1995).”
Therapeutic Approaches for the Treatment of Alzheimer's Disease: An Overview
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“Only one mouse exhibited accelerated tau deposition [80].”
Yu, J., Zhu, H., Taheri, S., Mondy, W. L., Perry, S. J., & Kindy, M. S. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1312-4 · Cited by 17 · see citing works
“The microglial activation and reactive astrocytosis are probably the result of the primary injury, the repetitive mTBI, and the consequences of a progressive, chronic neuroinflammatory condition that contributes to secondary and potentially tertiary responses [44].”
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- Authors
- Yoshiyama, Y., Uryu, K., Higuchi, M., Longhi, L., Hoover, R., Fujimoto, S., McIntosh, T., Lee, V. M.-Y., & Trojanowski, J. Q.
- Affiliations
- University of Pennsylvania (US)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- ORCID
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2005-10
- Volume
- 22
- Issue
- 10
- Pages
- 1134-1141
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- OpenAlex
- W2059869018
- Cited by
- 133
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 9 · 2019: 12 · 2018: 10 · 2017: 8 · 2016: 10 · 2015: 13 · 2014: 11 · 2013: 14 · 2012: 4
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurotrauma (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (P50NS008803, NS P50-08803, NS R01-40978)
- 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
- repetitive mild traumatic brain injury, chronic traumatic encephalopathy, neurofibrillary tangles, tau pathology, brain atrophy, cognitive impairment, concussion, Alzheimer's disease, transgenic mouse model, amyloid-beta, amyloid plaques
- MeSH terms
- Animals, Atrophy, Brain Injuries, Cerebral Cortex, Cognition Disorders, Disease Models, Animal, Humans, Immunohistochemistry, Mice, Transgenic, Blotting, Western, Neurofibrillary Tangles, tau Proteins, Maze Learning, Tauopathies, Mice
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