Experimental brain injury induces expression of amyloid precursor protein, which may be related to neuronal loss in the hippocampus
Abstract
Previous reports have demonstrated that some focal brain injuries increase amyloid precursor protein (APP) immunoreactivity in the region surrounding the injury where it was localized, in damaged axons and in pre-alpha 2 cells of the entorhinal cortex. However, to date, APP expression in the hippocampus remote from the impact site has not been comprehensively studied. Therefore, we have evaluated APP expression not only in the locally injured cerebral cortex but also in the hippocampus remote from the impact site. In the present paper, diffuse axonal injury was induced in rats in midline fluid percussion injury. APP expression was examined post injury using Western blot analysis and immunohistochemistry. Western blot analysis demonstrated that the expression of 100-kd APP was increased in both the cerebral cortex and hippocampus 24 h after injury. It then decreased in the hippocampus, but did not change in the cerebral cortex, 7 days after injury. Immunohistochemical studies showed increased immunoreactivity of APP in the neuronal perikarya and reactive astrocytes near the region of injury in the cerebral cortex 24 h to 7 days after injury. In the hippocampus, APP accumulated in the CA3 neurons 24 h and 3 days after injury, although no hemorrhagic lesions were seen at that site. The APP positive neurons in CA3 showed shrunken cell bodies and pyknotic nuclei 3 days after injury, and some of the neurons in CA3 had disappeared by 7 days postinjury. The results of present study s…
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APP expression increase after TBI has been replicated in multiple follow-up studies using CCI as well as midline and lateral FPI.
“which has been replicated in multiple follow-up studies using CCI as well as midline and lateral FPI (124–126).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [126]
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BackgroundRegion-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus
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“However, a certain degree of transcriptional regulation has been reported for APP and App mRNA in adult neurons following brain injury (Murakami et al., 1998; Van Den Heuvel et al., 1999, 2007; Itoh et al., 2009).”
BackgroundMALDI-imaging analyses of honeybee brains exposed to a neonicotinoid insecticide.
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“Therefore, the present study was designed to evaluate the temporal changes in ATP, glucose, and lactate levels at various intervals after CHI, in an attempt to correlate these changes with the changes in inflammatory mediators, which are major components in the pathophysiology of TBI.”
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“Penetrating needle, local head impact and other traumatic brain injuries stimulate APP immunoreactivity in damaged axons and reactive glial cells [112-115].”
BackgroundUpregulation of APP, ADAM10 and ADAM17 in the Denervated Mouse Dentate Gyrus
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“, [18]) and that processing of APP along the amyloidogenic pathway can result in an increased Aß deposition in brain [19].”
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“Over-expression of APP was found in aged motor neurons, in developing spinal motor neurons undergoing programmed cell death, as well as in damaged or injured neurons[6,7].”
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“Ischemia, hypoglycemia and traumatic brain injury, a condition that has been shown to put neurons under metabolic stress [131], all upregulate A β PP and/or its mRNA in animal models and culture systems [1,46,59,89,108–110 , 136].”
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“Therefore, other phenomena—such as APP deposition 59,60 delayed death of neurons, 59,61 the presence of less healthy neurons and reduced capacity of neurogenesis in the contralateral hippocampus, 62,63 demyelination—associated with delayed white matter damage on the uninjured side 64 may contribute…”
Lee, H., Petersen, R. B., Zhu, X., Honda, K., Aliev, G., Smith, M. A., & Perry, G. L. (2003) · Brain Pathology · doi:10.1111/j.1750-3639.2003.tb00491.x · Cited by 24 · see citing works
“(112), all upregulate A PP and its mRNA in animal models and cell culture systems (34, 44, 66, 91, 92, 116).”
BackgroundItoh, T., Satou, T., Nishida, S., Tsubaki, M., Hashimoto, S., & Ito, H. (2009) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-008-0013-1 · Cited by 17 · see citing works
“Therefore, the overexpression of APP is an important factor in the neuronal degeneration observed in AD [6].”
BackgroundEffect of impact on different regions of the head of lambs.
Finnie, J., van den Heuvel, C., Gebski, V., Manavis, J., Summersides, G., & Blumbergs, P. (2001) · Journal of Comparative Pathology · doi:10.1053/jcpa.2000.0446 · Cited by 17 · see citing works
Novel therapies for combating chronic neuropathological sequelae of TBI
Ikonomović, M. D., Abrahamson, E. E., Carlson, S. W., Graham, S. H., & Dixon, C. E. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.06.021 · Cited by 16 · see citing works
“APP mRNA and protein expression is upregulated acutely after experimental TBI (Ciallella et al., 2002; Murakami et al., 1998; Pierce et al., 1996), resulting in axonal accumulation of APP (Gentleman et al.”
Finnie, J. W., Manavis, J., Blumbergs, P., & Kuchel, T. (2000) · Veterinary Pathology-Supplement · doi:10.1354/vp.37-6-677 · Cited by 14 · see citing works
Tolédano, A., Alvarez, M. I., Rivas, L., Lacruz, C. R., & Martínez-Rodríguez, R. (1999) · Journal of Neural Transmission · doi:10.1007/s007020050231 · Cited by 10 · see citing works
“The factors associated with amyloid deposition, which include lesions, glial responses, reduction in blood flow, perturbed energy metabolism, free radicals, cations, NGF, ras, neurotransmitters or neuromodulators, cytokines, some proteins such as apolipoprotein E4 (Apo-E4), are poorly understood (Cosgaya et al., 1996;…”
BackgroundInfluentialSpatial and temporal dynamics of HDACs class IIa following mild traumatic brain injury in adult rats
Kamal, S., Potukutchi, S., Gelovani, D. J., Bonomi, R. E., Kallakuri, S., Cavanaugh, J., Mangner, T., Conti, A., Liu, R.-S., Pasqualini, R., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01369-7 · Cited by 10 · see citing works
“The volume of distribution (VD) of [(18)F]TFAHA in different brain structures was calculated using Logan graphical analysis [46, 67, 69–71] with frontal cortex as the reference tissue [46, 72].”
MethodBeitchman, J. A., Lifshitz, J., Harris, N., Thomas, T. C., Lafrenaye, A. D., Hånell, A., Dixon, C. E., Povlishock, J., & Rowe, R. K. (2020) · bioRxiv · doi:10.1089/neur.2020.0046 · Cited by 10 · see citing works
Srinivasan, G. R., & Brafman, D. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.813544 · Cited by 10 · see citing works
“Similarly, in a rat mFPI model APP immunoreactivity was observed to increase acutely in the hippocampus but decrease by 7 days post-injury which could be attributed to the cell death observed at this time point (Murakami et al., 1998).”
BackgroundMCP-1-Induced Migration of NT2 Neuroprogenitor Cells Involving APP Signaling
Vrotsos, E., & Sugaya, K. (2009) · Cellular and molecular neurobiology · doi:10.1007/s10571-008-9329-3 · Cited by 8 · see citing works
“Other studies report that traumatic brain injury can induce expression of APP (Pierce et al. 1996; Murakami et al. 1998; Ciallella et al. 2002).”
BackgroundSoni, N., Medeiros, R., Alateeq, K., To, X. V., & Nasrallah, F. A. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.611451 · Cited by 8 · see citing works
“Astrogliosis, microgliosis, and axonal injury generally occur together as a consequence of TBI in mice (Namjoshi et al., 2016, 2017; Bashir et al., 2020; To et al., 2020).”
BackgroundPathological Links between Traumatic Brain Injury and Dementia: Australian Pre-Clinical Research
Collins, J. M., Woodhouse, A., Bye, N., Vickers, J. C., King, A. E., & Ziebell, J. M. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2019.6906 · Cited by 7 · see citing works
“27 However, Australian neurotrauma researchers 89,97 and others 26,87,88 have also demonstrated an increase in neuronal APP staining after TBI.”
NGF and APP Interplay: Focus on YENPTY Motif of Amyloid Precursor Protein and Y682 Residue
Basso, E., & Matrone, C. (2013) · doi:10.4172/2324-9293.1000106 · Cited by 7
“Increased APP protein levels were found in regenerating neurons in Drosophila [46,47] and various mice models after brain injury [48-50].”
BackgroundCaMKII mechanisms that promote pathological LTP impairments
Larsen, M. E., Rumian, N. L., Quillinan, N., & Bayer, K. U. (2025) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2024.102961 · Cited by 6 · see citing works
“…agent in Alzheimer’s disease (AD) [12 e 14], but increased expression of A b and/or the A b precursor protein (APP) is also seen in Down syndrome (DS) [15 e 17], traumatic brain injury (TBI) [18 e 20], focal cerebral ischemia (stroke) [21 e 23], and global cerebral ischemia (GCI) [24 e 26].”
Expression and Cerebral Function of Amyloid Precursor Protein After Rat Traumatic Brain Injury
Itoh, T., Imano, M., Nishida, S., Tsubaki, M., Hashimoto, S., Ito, A., & Satou, T. (2011) · InTech eBooks · doi:10.5772/18814 · Cited by 2 · see citing works
“(Murakami et al., 1998).”
Walter, G. F. (2000) · doi:10.1007/s003290050157 · Cited by 2
Panegyres, P. K., & Atkins, E. (2011) · Neuroscience & Medicine · doi:10.4236/nm.2011.23033
“Penetrating needle, local head impact and other traumatic brain injuries stimulate APP immunoreactivity in damaged axons and reactive glial cells [112-115].”
Role of BACE1 in Cognitive Function, from Alzheimer’s Disease to Traumatic Brain Injury
Lombardo, S., & Tesco, G. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802851-3.00008-5 · Cited by 1 · see citing works
Padová, A., Rokytová, I., Mravec, B., Květňanský, R., & Vargovič, P. (2019) · Endocrine Regulations · doi:10.2478/enr-2019-0012
The effect of high glucose on APP metabolism and Abeta production
Yang, Y. (2013) · Joint Conference of the Information Retrieval Communities in Europe · doi:10.14288/1.0073763
“In adult animals, APP expression is enhanced after traumatic brain injury, indicating APP might be involved in brain repair (Itoh et al., 2009; Leyssen et al., 2005; Murakami et al., 1998; Van den Heuvel et al., 1999).”
Traumatic Brain Injury Pathophysiology/Models
Walker, P. A., & Allison, N. D. (2010) · Humana Press eBooks · doi:10.1007/978-1-60761-965-9_5
“Recent studies have shown increased levels of serum myelin basic protein (MBP), neuron specific enolase (NSE), a amyloid, and the biomarker S100B after TBI in a pediatric population (Berger et al. 2005, 2007; Murakami et al. 1998 ).”
BackgroundStem Cell Therapy in Alzheimer’s Disease
Sugaya, K., Kwak, Y.-D., & Alvarez, A. (2008) · doi:10.1007/978-0-387-72076-0_25
Stem Cell Therapy for Alzheimer’s Disease
Sugaya, K. (2004) · doi:10.1007/978-1-59259-661-4_33
Tarsy, D. (2004) · Current Clinical Neurology · doi:10.1007/978-1-59259-661-4
- Authors
- MURAKAMI, N., YAMAKI, T., IWAMOTO, Y., SAKAKIBARA, T., KOBORI, N., FUSHIKI, S., & UEDA, S.
- Affiliations
- Kyoto Prefectural University of Medicine (JP)
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 1998-11
- Volume
- 15
- Issue
- 11
- Pages
- 993-1003
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- OpenAlex
- W2048397152
- Cited by
- 100
- References
- 0
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 6 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 6 · 2013: 3 · 2012: 7
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurotrauma (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- amyloid precursor protein, traumatic brain injury, fluid percussion injury, hippocampus, CA3 neurons, neuronal loss, diffuse axonal injury, reactive astrocytes, cerebral cortex, APP overexpression, neurodegeneration
- MeSH terms
- Animals, Brain Injuries, Brain Stem, Corpus Callosum, Disease Models, Animal, Hippocampus, Immunohistochemistry, Male, Nerve Degeneration, Neurons, Nissl Bodies, Peptide Fragments, Time Factors, Blotting, Western, Amyloid beta-Peptides, Rats, Wistar, Rats
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