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Brain Trauma Induces Massive Hippocampal Neuron Death Linked to a Surge in β-Amyloid Levels in Mice Overexpressing Mutant Amyloid Precursor Protein
Open accessAbstract
Although brain trauma is a risk factor for Alzheimer's disease, no experimental model has been generated to explore this relationship. We developed a model of brain trauma in transgenic mice that overexpress mutant human amyloid precursor protein (PDAPP) leading to the appearance of Alzheimer's disease-like beta-amyloid (Abeta) plaques beginning at 6 months of age. We induced cortical impact brain injury in the PDAPP animals and their wild-type littermates at 4 months of age, ie, before Abeta plaque formation, and evaluated changes in posttraumatic memory function, histopathology, and regional tissue levels of the Abeta peptides Abeta1-40 and Abeta1-42. We found that noninjured PDAPP mice had impaired memory function compared to noninjured wild-type littermates (P < 0.01) and that brain-injured PDAPP mice had more profound memory dysfunction than brain-injured wild-type littermates (P < 0.001). Although no augmentation of Abeta plaque formation was observed in brain-injured PDAPP mice, a substantial exacerbation of neuron death was found in the hippocampus (P < 0.001) in association with an acute threefold increase in Abeta1-40 and sevenfold increase in Abeta1-42 levels selectively in the hippocampus (P < 0.01). These data suggest a mechanistic link between brain trauma and Abeta levels and the death of neurons.
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“Although CCI TBI induced a surge of plaque pathology in PDAPP mice soon after injury at 6 months of age, a substantial reduction in cortical and hippocampal plaque load was detected chronically (28, 40).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [28]
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“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 [28]
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Cites
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“These findings are potentially in contrast with studies of transgenic mice, where only overexpression of KPI(1) APP mRNA has been shown to induce persistent Ab production (40, 62, 63).”
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“This neuronal loss was accompanied by memory impairment, detected by the Morris Water Maze paradigm (Smith et al., 1998).”
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“Interestingly, it has been shown that acute Aβ accumulations can be reversed following TBI (Smith et al., 1998).”
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Behavioral consequences of minimal traumatic brain injury in mice.
Zohar, O., Rubovitch, V., Milman, A., Schreiber, S., & Pick, C. G. (2011) · Acta Neurobiologiae Experimentalis · doi:10.55782/ane-2011-1821 · Cited by 93
“Since immobility was suggested to reflect a state of depressive mood in mice (Smith et al. 1998), our results suggest that mice suffering from mTBI tend to develop a depressive-like behavior starting from 3 days after the injury.”
BackgroundResultBrain Trauma in Aged Transgenic Mice Induces Regression of Established Aβ Deposits
Nakagawa, Y., Reed, L., Nakamura, M., McIntosh, T. K., Smith, D. H., Saatman, K. E., Raghupathi, R., Clemens, J., Saido, T. C., Lee, V. M.-Y., et al. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7375 · Cited by 91
Self-citationAbrahamson, E. E., Ikonomovic, M. D., Ciallella, J. R., Hope, C. E., Paljug, W. R., Isanski, B. A., Flood, D. G., Clark, R. S. B., & DeKosky, S. T. (2006) · Experimental Neurology · doi:10.1016/j.expneurol.2005.10.011 · Cited by 90
Animal models of traumatic brain injury
Johnson, V. E., Meaney, D. F., Cullen, D. K., & Smith, D. H. (2015) · Handbook of clinical neurology · doi:10.1016/b978-0-444-52892-6.00008-8 · Cited by 151
“…the pathologic accumulation of proteins associated with chronic neurodegenerative disease, including amyloid beta and tau (Murai et al., 1998; Smith et al., 1998; Nakagawa et al., 1999, 2000; Hartman et al., 2002; Uryu et al., 2002; Yoshiyama et al., 2005; Abrahamson et al., 2006, 2009;…”
BackgroundSelf-citationOverexpression of Bcl-2 is neuroprotective after experimental brain injury in transgenic mice
Nakamura, M., Raghupathi, R., Merry, D. E., Scherbel, U., Saatman, K. E., & McIntosh, T. K. (1999) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19991004)412:4 · Cited by 81
Self-citationGonzalez-Lima, F., Berndt, J. D., Valla, J. E., Games, D., & Reiman, E. M. (2001) · Neuroreport · doi:10.1097/00001756-200108080-00018 · Cited by 62
Wu, Y., Bogale, T. A., Koıstınaho, J., Pizzi, M., Rõlova, T., & Bellucci, A. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02696-z · Cited by 82
“Similar acute A β accumulations accompanied by neuronal death and memory impairment have been reported in APP-transgenic mice subjected to TBI [123].”
BackgroundSuo, Z., Wu, M., Citron, B. A., Wong, G. T., & Festoff, B. W. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4856-03.2004 · Cited by 75
Kay, A. D., Petzold, A., Kerr, M., Keir, G., Thompson, E. J., & Nicoll, J. A. R. (2003) · Journal of Neurotrauma · doi:10.1089/089771503770195795 · Cited by 64
“…apoE participates in a coordinated response to brain injury, human in vivo evidence is lacking and the relevance of A b to the process of acute human brain injury is unknown (Horsburgh et al., 1997, 2000a,b; Horsburgh and Nicoll, 1996; Nakagawa et al., 1999; Smith et al., 1998; White et al., 2001).”
Myelin in Alzheimer’s disease: culprit or bystander?
Maitre, M., Jeltsch-David, H., Okechukwu, N. G., Klein, C., Patte-Mensah, C., & Mensah-Nyagan, A.-G. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01554-5 · Cited by 66
Gandy, S., Ikonomović, M. D., Mitsis, E. M., Elder, G. A., Ahlers, S. T., Barth, J. T., Stone, J. R., & DeKosky, S. T. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-37 · Cited by 68
Finnie, J. W., & Blumbergs, P. C. (2002) · Veterinary Pathology · doi:10.1354/vp.39-6-679 · Cited by 122
Traumatic brain injury induces biphasic upregulation of ApoE and ApoJ protein in rats
Iwata, A., Browne, K. D., Chen, X., Yuguchi, T., & Smith, D. H. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20607 · Cited by 53
“It has been found previously that TBI in rodent models induces remarkably progressive brain atrophy for at least 1 year postinjury (Smith et al., 1997, 1998; Dixon et al., 1999; Bramlett and Dietrich, 2002).”
BackgroundSelf-citationAtwood, C., Bowen, R. L., Smith, M. A., & Perry, G. L. (2003) · Brain Research Reviews · doi:10.1016/s0165-0173(03)00206-6 · Cited by 64
Rowe, R. K., Harrison, J., O'Hara, B., & Lifshitz, J. (2014) · Sleep · doi:10.5665/sleep.3582 · Cited by 62
Hopkins, R., Tate, D., & Bigler, E. (2005) · Neuropsychology · doi:10.1037/0894-4105.19.2.233 · Cited by 61
Hiltunen, M. O., van Groen, T., & Jolkkonen, J. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1154 · Cited by 62
“ciated memory impairment following TBI [101].”
Loane, D. J., Washington, P. M., Vardanian, L., Pocivavsek, A., Hoe, H.-S., Duff, K. E., Cernak, I., Rebeck, G. W., Faden, A. I., & Burns, M. P. (2011) · Journal of Neurotrauma · doi:10.1089/neu.2010.1595 · Cited by 57
“CCI in PDAPP mice causes a brief spike in Ab40 and Ab42, peaking at 2 h post-injury, and returning to baseline by 6 h (Smith et al., 1998).”
Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study
Mielke, M. M., Savica, R., Wiste, H. J., Weigand, S. D., Vemuri, P., Knopman, D. S., Lowe, V. J., Roberts, R. O., Machulda, M. M., Geda, Y. E., et al. (2013) · Neurology · doi:10.1212/01.wnl.0000438229.56094.54 · Cited by 59
Schwetye, K. E., Cirrito, J. R., Esparza, T. J., Mac Donald, C. L., Holtzman, D. M., & Brody, D. L. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.06.018 · Cited by 51
Cheng, W. H., Stukas, S. K., Martens, K. M., Namjoshi, D., Button, E. B., Wilkinson, A., Bashir, A., Robert, J., Cripton, P. A., & Wellington, C. L. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.12.007 · Cited by 46
Ikonomović, M. D., Mi, Z., & Abrahamson, E. E. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.11.003 · Cited by 53
Longhi, L. G., Saatman, K. E., Raghupathi, R., Laurer, H. L., Lenzlinger, P. M., Riess, P., Neugebauer, E. A. M., Trojanowski, J. Q., Lee, V. M. ‐., Grady, M. S., et al. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200111000-00001 · Cited by 51
Self-citationKokiko-Cochran, O., Ransohoff, L., Veenstra, M., Lee, S., Saber, M., Sikora, M., Teknipp, R., Xu, G., Bemiller, S., Wilson, G., et al. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2015.3970 · Cited by 49
The role of synaptic activity in the regulation of amyloid beta levels in Alzheimer's disease
Cheng, X., Wu, J., Geng, M., & Xiong, J. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.11.021 · Cited by 51
Traumatic Brain Injury: Methods for Clinical and Forensic Neuropsychiatric Assessment
Granacher, R. (2003) · doi:10.1201/9780203501740 · Cited by 47
Hånell, A., Clausen, F., Björk, M., Jansson, K., Philipson, O., Nilsson, L. N. G., Hillered, L., Weinreb, P. H., Lee, D. C., McIntosh, T. K., et al. (2010) · Journal of Neurotrauma · doi:10.1089/neu.2009.1255 · Cited by 39
“Following TBI in the mouse, no or only minimal increases of A b have previously been observed (Smith et al., 1998), and our results suggest that accumulation of A b deposition is not a major contributor to this TBI model, nor is A b the likely cause for the impaired cognitive function observed in…”
Self-citationPKC activator therapeutic for mild traumatic brain injury in mice
Zohar, O., Lavy, R., Zi, X., Nelson, T. J., Hongpaisan, J., Pick, C. G., & Alkon, D. L. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.10.001 · Cited by 53
“One of TBI's secondary consequences is increased synthesis and expression of the amyloid precursor protein (APP) and its proteolytic product βA, which is the main constituent of plaques observed in brains of Alzheimer's disease (AD) patients (Gorrie et al., 2002; Pierce et al., 1996; Lewen et al., 1995; Murai et al.,…”
BackgroundCollins, J. M., King, A. E., Woodhouse, A., Kirkcaldie, M. T. K., & Vickers, J. C. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.02.034 · Cited by 43
“PDAPP mice (APPV717F) subjected to CCI prior to the age-related deposition of plaques showed no subsequent change in plaque deposition at two months post-injury (Smith et al., 1998) but a decreased abundance of plaques at eight months post-injury (Nakagawa et al.”
Marchesi, V. T. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.03.004 · Cited by 36
van den Heuvel, C., Donkin, J., Finnie, J., Blumbergs, P., Kuchel, T., Koszyca, B., Manavis, J., Jones, N., Reilly, P., & Vink, R. (2004) · Journal of Neurotrauma · doi:10.1089/neu.2004.21.1562 · Cited by 39
“…that A (cid:1) deposition may occur more rapidly in predisposed transgenic mice overexpressing APP (Games et al., 1995; Johnson-Wood et al., 1997; Smith et al., 1998) and that overexpression of APP after TBI is a risk factor for the subsequent development of AD (Smith et al., 1998), the…”
Hanzel, D. K., Trojanowski, J. Q., Johnston, R. F., & Loring, J. F. (1999) · Nature Biotechnology · doi:10.1038/5225 · Cited by 38
Self-citationFunctional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice
Marklund, N., Morales, D. M., Clausen, F., Hånell, A., Kiwanuka, O., Pitkänen, A., Gimbel, D. A., Philipson, O., Lannfelt, L., Hillered, L., et al. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.06.042 · Cited by 38
Self-citationMolecular Pathology of Alzheimer’s Disease and Related Disorders
Ginsberg, S. D., Schmidt, M. L., Crino, P. B., Eberwine, J. H., Lee, V. M. ‐., & Trojanowski, J. Q. (1999) · Cerebral cortex · doi:10.1007/978-1-4615-4885-0_17 · Cited by 38
Self-citationKhodaie, B., Lotfinia, A. A., Ahmadi, M., Lotfinia, M., Jafarian, M., Karimzadeh, F., Coulon, P., & Gorji, A. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.09.034 · Cited by 41
Animal Models of Traumatically-Induced Dementia
Slemmer, J., Hossain, M. Z., & Weber, J. (2011) · Neuromethods · doi:10.1007/978-1-60761-898-0_32 · Cited by 34
Gene-Environment Interaction Research and Transgenic Mouse Models of Alzheimer's Disease (Erratum)
Chouliaras, L., Sierksma, A. S. R., Kenis, G., Prickaerts, J., Lemmens, M. A. M., Brasnjevic, I., van Donkelaar, E. L., Martínez‐Martínez, P., Losen, M. H., Baets, M. H. D., et al. (2010) · International Journal of Alzheimer s Disease · doi:10.4061/2010/356862 · Cited by 44
“TBI also resulted in hippocampal neuronal loss one week after injury, which was associated with an increase in hippocampal Aβ40 and Aβ42 [150].”
BackgroundInfluentialWhat Can Rodent Models Tell Us About Cognitive Decline in Alzheimer's Disease?
Davis, S., & Laroche, S. (2003) · Molecular Neurobiology · doi:10.1385/mn:27:3:249 · Cited by 32
Gene-Environment Interaction Research and Transgenic Mouse Models of Alzheimer's Disease
Chouliaras, L., Sierksma, A. S. R., Kenis, G., Prickaerts, J., Lemmens, M. A. M., Brasnjevic, I., van Donkelaar, E. L., Martínez‐Martínez, P., Losen, M. H., Baets, M. H. D., et al. (2010) · International Journal of Alzheimer s Disease · doi:10.4061/2010/859101 · Cited by 30
“TBI also resulted in hippocampal neuronal loss one week after injury, which was associated with an increase in hippocampal Aβ40 and Aβ42 [150].”
BackgroundInfluentialMechanical stress increases brain amyloid β, tau, and α‐synuclein concentrations in wild‐type mice
Lévy, M., Hamraz, M., Abolhassani, M., Bigan, E., Lafitte, O. D., Steyaert, J., Dubois, B., & Schwartz, L. H. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.11.003 · Cited by 29
“Controlled cortical impact injury, in turn, can induce a two to threefold increase in Ab1–42 in APP transgenic mice [29,30] and a 50% increase in Ab1–42 in wild-type mice.”
BackgroundPortbury, S. D., & Adlard, P. A. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-143048 · Cited by 26
“in memory impairment) [67].”
The Neurovascular Unit as a Locus of Injury in Low-Level Blast-Induced Neurotrauma
Elder, G. A., Sosa, M. A. G., Gasperi, R. D., Garcia, G. S. P., Perez, G. M., Abutarboush, R., Kawoos, U., Zhu, C. W., Janssen, W. G. M., Stone, J. R., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25021150 · Cited by 25
Metadata
- Authors
- Smith, D. H., Nakamura, M., McIntosh, T. K., Wang, J., Rodríguez, A., Chen, X.-H., Raghupathi, R., Saatman, K. E., Clemens, J., Schmidt, M. L., Lee, V. M.-Y., & Trojanowski, J. Q.
- Affiliations
- University of Pennsylvania (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Smith, Douglas H.
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 1998-09
- Volume
- 153
- Issue
- 3
- Pages
- 1005-1010
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1853010
- OpenAlex
- W2028535633
- Cited by
- 143
- References
- 28
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 4 · 2014: 7 · 2013: 9 · 2012: 3
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services (85-23)
- University of Pennsylvania
- National Institute on Aging (AG12527, P01AG011542, AG09215, R01AG012527, P01AG009215, AG 11542)
- National Institute of Neurological Disorders and Stroke (P50NS008803)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- traumatic brain injury, Alzheimer's disease, amyloid precursor protein, amyloid-beta, Aβ40, amyloid-beta 42, memory impairment, cortical impact injury, amyloid plaques
- MeSH terms
- Animals, Brain Injuries, Disease Models, Animal, Female, Hippocampus, Mice, Transgenic, Neurons, Ovariectomy, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cell Death, Maze Learning, Mice
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