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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
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
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“In this study we also found that PDAPP mice demonstrate memory dysfunction before the appearance of overt AD-like pathology, consistent with previous reports using other transgenic mouse strains.(20,21) Although there appeared to be an exacerbation of posttraumatic memory dysfunction in the PDAPP mice compared to wild…”
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“Indeed, a single incident of brain trauma may result in a widespread deposition of Ab,(3,4) and a history of brain trauma increases an individual’s risk for AD.(5) Moreover, marked accumulations of b-amyloid precursor proteins have been seen after brain trauma in humans and experimental animals.”
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Background
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Items 101–135 of 135
López-Rodríguez, A. B., Mela, V., Acaz‐Fonseca, E., García‐Segura, L. M., & Viveros, M. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.03.018 · Cited by 23
“, 2014) and that elevated β-APP is associated with neuronal death, behavioral dysfunction (Mattson, 2004) and cognitive deficit in a TBI model (Smith et al., 1998).”
Cerebral Blood Flow Changes after Brain Injury in Human Amyloid-Beta Knock-in Mice
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Self-citationBeneficial effect of amyloid beta after controlled cortical impact
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Bachstetter, A. D., Garrett, F. G., Jicha, G. A., & Nelson, P. T. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01152-3 · Cited by 20
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Backgroundvan den Heuvel, C., Finnie, J., Blumbergs, P., Manavis, J., Jones, N., Reilly, P., & Pereira, R. A. (2000) · Journal of Neurotrauma · doi:10.1089/neu.2000.17.1041 · Cited by 16
“…it may also be deleterious in that there is evidence that )3A4 deposition may occur more rapidly in predisposed transgenic mice over-expressing APP (Games et al., 1995; Johnson-Wood et al., 1997; Smith et al., 1998) and TBI is a risk factor for the subsequent development of AD (Smith et al., 1998).”
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
“20–26 Collectively, these findings suggest that upregulation of APP and its processing enzymes may cause increased A b production and explain the epidemiological associations between TBI and AD.”
Villarreal, A. E., Barron, R., Rao, K. S. J., & Britton, G. B. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140144 · Cited by 14
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Ye, X., Chen, J., Pan, J., Wu, Q., Wang, Y., Lu, M., Zhang, C., Zhang, Z., Ma, M., Zhu, J., et al. (2022) · Immunological Investigations · doi:10.1080/08820139.2022.2136525 · Cited by 18
“On the other hand, IL-17 may also be upregulated when the CNS is stressed, such as during brain trauma or infections that are linked to AD (Kumar et al. 2016; Smith et al. 1998; Victoria et al. 2010).”
BackgroundTherapeutic Approaches for the Treatment of Alzheimer's Disease: An Overview
Lau, L., & Brodney, M. A. (2007) · Springer eBooks · doi:10.1007/7355_2007_017 · Cited by 8
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“Furthermore, in transgenic mice models, an association was found between elevated hippocampal Aβ levels and neuronal cell death after TBI (Smith et al., 1998).”
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Neuropathology of Traumatic Brain Injury and Its Role in the Development of Alzheimer’s Disease
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“However, brain trauma induces massive hippocampal neuronal loss linked to a surge in beta amyloid levels in the PDAPP mouse [25].”
Tran, H. (2011) · Open Scholarship Institutional Repository (Washington University in St. Louis) · doi:10.7936/k7gb223z
“overexpress either mutated forms of APP or tau, not both (Smith et al., 1998; Uryu et al., 2002; Yoshiyama et al., 2005).”
BackgroundResultInfluentialTseitlin, L., Schreiber, S., Richmond-Hacham, B., Bikovski, L., & Pick, C. G. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.115069 · Cited by 6
Recent insights from non-mammalian models of brain injuries: an emerging literature
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“Additionally,massivehippocampalneuronaldeathwithassociatedcog-nitive impairment was observed in transgenic TBI mice overexpressing mutant APP with elevated A β level (Figure 3) (Smith et al., 1998).”
BackgroundTraumatic 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
Early Aβ42 Exposure Causes Learning Impairment in Later Life
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Self-citation
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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