The DOI matches its Crossref record; 25 of the 28 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“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]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210 · cited 2×
“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…”
BackgroundResultAlzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein
Games, D., Adams, D., Alessandrini, R., Barbour, R., Borthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al. (1995) · Nature · doi:10.1038/373523a0 · Cited by 2,516
Self-citationIwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N., & Ihara, Y. (1994) · Neuron · doi:10.1016/0896-6273(94)90458-8 · Cited by 1,774
Suzuki, N., Cheung, T. T., Cai, X.-D., Odaka, A., Otvos, L., Eckman, C., Golde, T. E., & Younkin, S. G. (1994) · Science · doi:10.1126/science.8191290 · Cited by 1,471
Association of apolipoprotein E polymorphism with outcome after head injury
Teasdale, G. M., Nicoll, J. A. R., Murray, G. D., & Fiddes, M. (1997) · The Lancet · doi:10.1016/s0140-6736(97)04318-3 · Cited by 683
IRIZARRY, M. C., MCNAMARA, M., FEDORCHAK, K., HSIAO, K., & HYMAN, B. T. (1997) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199709000-00002 · Cited by 649
Mortimer, J. A., Van Duijn, C. M., Chandra, V, Fratiglioni, L., Graves, A. B., Heyman, A., Jorm, A. F., Kokmen, E., Kondo, K., Rocca, W. A., et al. (1991) · International Journal of Epidemiology · doi:10.1093/ije/20.supplement_2.s28 · Cited by 594 · cited 2×
“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.”
BackgroundMayeux, R., Ottman, R., Maestre, G., Ngai, C., Tang, M.-X., Ginsberg, H., Chun, M., Tycko, B., & Shelanski, M. (1995) · Neurology · doi:10.1212/wnl.45.3.555 · Cited by 590
(1997) · doi:10.1073/pnas.94.4.1550 · Cited by 535
The occult aftermath of boxing.
Roberts, G. W., Allsop, D., & Bruton, C. (1990) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.53.5.373 · Cited by 518 · cited 1×
“Previously, postmortem histopathological analysis of brains from boxers with dementia pugilistica (punch-drunk syndrome) revealed neurofibrillary tangles and diffuse plaques composed of b-amyloid peptides (Abs) similar to AD lesions.(1,2) Indeed, a single incident of brain trauma may result in a widespread deposition…”
BackgroundIrizarry, M. C., Soriano, F., McNamara, M., Page, K. J., Schenk, D., Games, D., & Hyman, B. T. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-18-07053.1997 · Cited by 497
Apolipoprotein E ε4 allele is associated with deposition of amyloid β-protein following head injury
Nicoll, J. A. R., Roberts, G. W., & Graham, D. I. (1995) · Nature Medicine · doi:10.1038/nm0295-135 · Cited by 486
SMITH, D. H., SOARES, H. D., PIERCE, J. S., PERLMAN, K. G., SAATMAN, K. E., MEANEY, D. F., DIXON, C. E., & McINTOSH, T. K. (1995) · Journal of Neurotrauma · doi:10.1089/neu.1995.12.169 · Cited by 451 · cited 4×
“The water maze paradigm has been described in detail.(12,13) Briefly, the water maze is a circular pool 1 m in diameter.”
MethodResultInfluentialSelf-citationβA4 amyloid protein deposition in brain after head trauma
Roberts, G., Gentleman, S., Lynch, A., & Graham, D. I. (1991) · The Lancet · doi:10.1016/0140-6736(91)92724-g · Cited by 440
Evaluation of Memory Dysfunction Following Experimental Brain Injury Using the Morris Water Maze
Smith, D. H., Okiyama, K., Thomas, M. J., CLAUSSEN, B., & McINTOSH, T. K. (1991) · Journal of Neurotrauma · doi:10.1089/neu.1991.8.259 · Cited by 351 · cited 1×
“The water maze paradigm has been described in detail.(12,13) Briefly, the water maze is a circular pool 1 m in diameter.”
MethodSelf-citationNalbantoglu, J. N., Santiago, G. T., Lahsaïni, A., Poirier, J., Goncalves, O., Verge, G. M., Momoli, F., Welner, S. A., Massicotte, G., Julien, J., et al. (1997) · Nature · doi:10.1038/387500a0 · Cited by 342 · cited 1×
“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…”
ResultPierce, J., Trojanowski, J., Graham, D., Smith, D., & McIntosh, T. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-03-01083.1996 · Cited by 239
Self-citationBRAMLETT, H. M., KRAYDIEH, S., GREEN, E. J., & DIETRICH, W. D. (1997) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199710000-00007 · Cited by 225 · cited 1×
“Moreover, marked accumulations of b-amyloid precursor proteins have been seen after brain trauma in humans and experimental animals.(6,7,8,9) Although this suggests that ample substrates are available for pathological Ab production after trauma, the investigation of mechanisms whereby brain trauma induces deposition o…”
BackgroundZhang, F., Eckman, C., Younkin, S., Hsiao, K. K., & Iadecola, C. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-20-07655.1997 · Cited by 205 · cited 2×
“In support of this hypothesis, a very recent report demonstrated increased susceptibility to ischemic brain damage in another line of transgenic mice overexpressing mutant APP.(26) Although there was no difference in Ab levels between ischemic and nonischemic hemispheres at 24 hours postinjury, high baseline levels of…”
ResultTurner, R. S., Suzuki, N., Chyung, A. S. C., Younkin, S. G., & Lee, V. M.-Y. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.15.8966 · Cited by 161
Self-citationDistribution of β‐amyloid protein in the brain following severe head injury
Graham, D. I., Gentleman, S., Lynch, A., & Roberts, G. (1995) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1995.tb01025.x · Cited by 140
Lack of alzheimer pathology after β-amyloid protein injections in rat brain
Games, D., Khan, K., Soriano, F., Keim, P. S., Davis, D. L., Bryant, K., & Lieberburg, I. M. (1992) · Neurobiology of Aging · doi:10.1016/0197-4580(92)90057-5 · Cited by 127
Traumatic brain injury in rat produces changes of beta-amyloid precursor protein immunoreactivity.
Lewén, A., Li, G., Nilsson, P., Olsson, Y., & Hillered, L. (1995) · NeuroReport · doi:10.1097/00001756-199501000-00032 · Cited by 95 · cited 2×
“Although this suggests that ample substrates are available for pathological Ab production after trauma, the investigation of mechanisms whereby brain trauma induces deposition of Ab has been hampered by the inability of experimental models of brain trauma in rodents to produce Ab-containing plaques.(6,7) Although ther…”
BackgroundSchmidt, M. L., Didario, A. G., Lee, V. M. ‐., & Trojanowski, J. Q. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)00259-2 · Cited by 47
Self-citationStephenson, D. T., & Clemens, J. A. (1992) · Brain Research · doi:10.1016/0006-8993(92)91632-o · Cited by 22 · cited 1×
“However, hippocampal neuron death has never been reported in the absence of brain injury in this or another line of transgenic mice that overexpress mutant b-amyloid precursor proteins and develop increasing numbers of AD-like amyloid plaques with advancing age(22,23) Moreover, no induction of neuron death has been se…”
BackgroundSelf-citation
Research works printed but not linked: 3
- Tokuda, 1991, Re-examination of ex-boxers' brains using immunohistochemistry with antibodies to amyloid β-protein and tau protein, Acta Neuropathol, 82, 281, 10.1007/BF00308813 · DOI
- Sherriff, 1994, Early detection of axonal injury after human head trauma using immunocytochemistry for β-amyloid precursor protein, Acta Neuropathol, 87, 55, 10.1007/BF00386254 · DOI
- Standaert, 1991, Molecular features of hypothalamic plaques in Alzheimer's disease, Am J Pathol, 139, 681
Cited by
Sorted by citations
Chronic traumatic encephalopathy in athletes: Progressive tauopathy after repetitive head injury
McKee, A. C., Cantu, R. C., Nowinski, C. J., Hedley-Whyte, E. T., Gavett, B. E., Budson, A. E., Santini, V. E., Lee, H.-S., Kubilus, C. A., & Stern, R. A. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181a9d503 · Cited by 2,295
“Increased amyloid precursor protein production in experimental TBI has also been associated with heightened neuronal loss in the hippocampus (73, 79).”
BackgroundDiabetes mellitus and the risk of dementia: The Rotterdam Study
Ott, A., Stolk, R. P., van Harskamp, F., Pols, H. A. P., Hofman, A., & Breteler, M. M. B. (1999) · Neurology · doi:10.1212/wnl.53.9.1937 · Cited by 2,175
Blennow, K., Brody, D. L., Kochanek, P. M., Levin, H. S., McKee, A. C., Ribbers, G. M., Yaffe, K. S., & Zetterberg, H. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.84 · Cited by 693
Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences
Bramlett, H., & Dietrich, W. (2004) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1097/01.wcb.0000111614.19196.04 · Cited by 622
“In mouse studies, 10- fold over-expression of mutant APP leads to the development of plaques at 6 months of age, with TBI exacerbating cognitive impairments and hippocampal CA3 pathology compared with littermates (Smith et al., 1998).”
BackgroundTraumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease?
Johnson, V. E., Stewart, W., & Smith, D. H. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2808 · Cited by 587
“TBI before plaque formation induced a surge in the tissue concentration of Aβ that was associated with an increase in hippocampal neuronal death and memory impairment, indicating the potential toxicity of A&beta”
BackgroundSelf-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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
