Changes in Expression of Amyloid Precursor Protein and Interleukin-1β after Experimental Traumatic Brain Injury in Rats
Abstract
There is increasing evidence linking neurodegenerative mechanisms in Alzheimer's disease (AD) and traumatic brain injury (TBI), including increased production of amyloid precursor protein (APP), and amyloid-beta (Abeta) peptide. In vitro data indicate that expression of APP may be regulated in part by the inflammatory cytokine IL-1beta. To further investigate the mechanisms involved, we measured APP and IL-1beta protein levels and examined immunohistochemical localization of APP in brain tissue from rats subjected to controlled cortical impact (CCI) injury. Animals were examined at time intervals ranging from 3 h to 4 weeks after TBI. The 24-h time point revealed a dramatic increase in APP immunoreactivity, detected with both N- and C-terminal antibodies, in the hippocampus and cortex ipsilateral to injury. This finding was sustained up to 3 days post-injury. At these early time points, APP increase was particularly robust in the white matter axonal tracts. By 14 days after injury, APP immunoreactivity was not significantly different from sham controls in cortex, but remained slightly elevated in hippocampus. Western blot data corroborated early increases in hippocampal and cortical APP in injured versus control animals. Despite profound APP changes, no Abeta deposits were observed at any time after injury. Hippocampal and cortical IL-1beta increases were even more robust, with IL-1beta levels peaking by 6 h post-injury and returning to baseline by 24-72 h. Our results demons…
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A majority of rodent studies fail to show Aβ deposition after TBI in non-transgenic animals using CCI, FPI, and weight drop models.
“a majority of rodent studies fail to show this association in non-transgenic animals using CCI, FPI, and weight drop models (121, 122, 124, 125, 135).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [124]
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 [124]
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“Less is known about the effects of IL-1b in diffuse TBI, although increased expression of IL-1b was associated with axonal injury (Ciallella et al., 2002; Campbell et al., 2007).”
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“Whilst neuropathology and gliosis have been observed to subside in the few weeks to months following brain injury compared with higher levels at acute time points (3, 96).”
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The effect of Boswellia Serrata on neurorecovery following diffuse axonal injury
Moein, P., Abbasifard, S., Asnaashari, A., Baratian, H., Barekatain, M., Tavakoli, N., & Moein, H. (2013) · Brain Injury · doi:10.3109/02699052.2013.825009 · Cited by 21
Jalin, A. M. A. A., Jin, R., Wang, M., & Li, G. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.01.002 · Cited by 18 · see citing works
“It has been shown that TBI induces β-APP overexpression and Aβ accumulation which peaked at 1–3 days after injury in rodents (Ciallella et al., 2002; Loane et al., 2011).”
BackgroundDing, X., Cao, S., Wang, Q., Du, B., Lu, K., Qi, S., Cheng, Y., Tuo, Q., Liang, W., & Lei, P. (2024) · Advanced Science · doi:10.1002/advs.202306399 · Cited by 14 · see citing works
The Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer’s Disease
Busch, L., Eggert, S., Endres, K., & Bufe, B. (2022) · Cells · doi:10.3390/cells11213421 · Cited by 19 · see citing works
Effects of Memantine in a Mouse Model of Postoperative Cognitive Dysfunction
Almahozi, A., Radhi, M. A., Alzayer, S., & Kamal, A. (2019) · Behavioral Sciences · doi:10.3390/bs9030024 · Cited by 17 · see citing works
“Additionally, amyloid precursor protein (APP), whose proteolysis leads to the generation of beta-amyloid proteins and acts as an acute reactive protein during stress [103,104], was also found to be increased following surgery in mice [25].”
BackgroundChiu, L. S., Anderton, R. S., Knuckey, N. W., & Meloni, B. P. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0287-3 · Cited by 14 · see citing works
Therapeutic Potentials of Synapses after Traumatic Brain Injury: A Comprehensive Review
Wen, Z., Li, D., Shen, M., & Chen, G. (2017) · Neural Plasticity · doi:10.1155/2017/4296075 · Cited by 11 · see citing works
“A body of proinflammatory cytokines are rapidly elevated in the acute period including IL-6, TNF-α, and so on [36]; besides, the increased cytokines levels in the brain are dramatically higher than the corresponding levels in serum [37].”
BackgroundClinical Traumatic Brain Injury in the Preclinical Setting
Berkner, J., Mannix, R., & Qiu, J. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3816-2_2 · Cited by 20 · see citing works
Age Moderates the Effects of Traumatic Brain Injury on Beta-Amyloid Plaque Load in APP/PS1 Mice
Collins, J. M., King, A. E., Woodhouse, A., Kirkcaldie, M., & Vickers, J. C. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.5982 · Cited by 16 · 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., 1993; Ikonomovic et al., 2004; McKenzie et al., 1994) which was linked to subsequent…”
Self-citationAgrawal, R., Larrea, D., Xu, Y., Shi, L., Zirpoli, H., Cummins, L., Emmanuele, V., Song, D., Yun, T. D., Macaluso, F., et al. (2020) · bioRxiv · doi:10.1007/s10571-022-01299-0 · Cited by 13 · see citing works
“…finding has has been reported in TBI studies as well (Chen et al 2004; Cartagena et al 2016) and has been attributed to elevated expression of APP (C99 precursor) and BACE1 (the enzyme that cleaves APP to form C99) in damaged brain areas (Ciallella et al 2002; Blasko et al 2004; Chen et al 2004).”
BackgroundMarklund, N., Sihver, S., Hovda, D., Långström, B., Watanabe, Y., Ronquist, G., Bergström, M., & Hillered, L. (2009) · Journal of Neurotrauma · doi:10.1089/neu.2008.0827 · Cited by 13 · see citing works
Koh, H., Hwang, K., Lim, H.-Y., Kim, Y.-J., & Lee, Y.-H. (2015) · Neural Regeneration Research · doi:10.4103/1673-5374.172321 · Cited by 11 · see citing works
“Increased concentrations of TNF-α after diffuse axonal injury in head trauma imply that TNF-α participates in secondary neuronal injury (Ciallella et al., 2002; Campbell et al., 2007; Lin et al., 2013).”
BackgroundSpatial 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
“Similar to our current experimental findings, other reports demonstrated an increased accumulation of APP in the hippocampus (predominantly in the CA3 region) and in the cerebral cortex during the acute phase post mTBI [73, 76, 80].”
ResultTsui, C. T., MacGillivray, S. R., Weber, S. M., McAllister, L., Churchward, M. A., Dennison, C. R., & Todd, K. G. (2020) · Journal of the mechanical behavior of biomedical materials/Journal of mechanical behavior of biomedical materials · doi:10.1016/j.jmbbm.2020.104176 · Cited by 11 · see citing works
Dropping the BACE: Beta Secretase (BACE1) as an Alzheimer’s Disease Intervention Target
Read, J. L., & Suphioglu, C. (2013) · InTech eBooks · doi:10.5772/53603 · Cited by 6 · see citing works
“Additionally, the APP mRNA translation is upregulated in the event of trauma, nerve damage and brain ischemia, which can be beneficial for the release of more AICD, but can also result in the production of more Aβ [71-73].”
Srinivasan, G. R., & Brafman, D. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.813544 · Cited by 10 · see citing works
Abrahamson, E. E., Poloyac, S. M., Dixon, C. E., DeKosky, S. T., & Ikonomović, M. D. (2019) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-190909 · Cited by 9 · see citing works
“Sections were processed using the avidin-biotin method as described previously (Ciallella et al., 2002), with a mouse monoclonal antibody directed against synaptophysin (Sigma, #S5768, clone SVP-38, RRID:AB 477523; lots 118K4828, 127K4819, and 027K4834), an affinity-purified, biotinylated goat…”
Self-citationMCP-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).”
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.”
Kim, S., Seo, C., Park, H., Kwon, J., Kim, J. K., Moon, H., Lim, S., Gho, Y., Lee, W.-J., Choi, Y.-M., et al. (2024) · Perspectives on Integrative Medicine · doi:10.56986/pim.2024.06.007 · Cited by 5
“IL-1 β , a key mediator of the inflammatory response, exacerbates damage during chronic disease, and acute tissue injury [29].”
BackgroundThe Function of the Amyloid Precursor Protein Family
Cappai, R., Needham, B. E., & Ciccotosto, G. D. (2006) · Springer eBooks · doi:10.1007/978-1-84628-440-3_3 · Cited by 5 · see citing works
“The in vivo relevance of this activity is supported by endogenous APP being upregulated after brain injury with strong immunoreactivity being present in both human and experimental models of head injury [43, 94, 95, 96].”
Beach, T. G., Deture, M. A., Walker, J. E., Arce, R. A., Glass, M. J., Sue, L. I., Intorcia, A. J., Nelson, C. M., Suszczewicz, K. E., Borja, C. I., et al. (2021) · medRxiv · doi:10.1101/2021.12.16.21266656 · Cited by 3 · see citing works
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
“It was previously reported that APP mRNA and protein levels were increased in neurons after TBI (Van den Heuvel et al., 1999; Ciallella et al., 2002).”
A protective role for APP in nuclear waste clearance via lysosomal exocytosis
Dougnon, G., Otsuka, T., Nakamura, Y., Sakai, A., Yamanaka, T., Matsui, N., Nakahara, A., Ito, A., Hatano, A., Matsumoto, M., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2524190123 · Cited by 4 · see citing works
Montivero, A., Ghersi, M., Catalan, J., Formica, M. L., Camacho, N., Culasso, A. F., Hereñú, C. B., Palma, S. D., & Pérez, M. F. (2021) · Springer eBooks · doi:10.1007/978-3-030-61721-9_20 · Cited by 1 · see citing works
AdamsMD (2003) · doi:10.1097/01.wco.0000084234.82329.c0
- Authors
- Ciallella, J. R., Ikonomovic, M. D., Paljug, W. R., Wilbur, Y. I., Dixon, C. E., Kochanek, P. M., Marion, D. W., & DeKosky, S. T.
- Affiliations
- University of Pittsburgh Medical Center (US)
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2002-12
- Volume
- 19
- Issue
- 12
- Pages
- 1555-1567
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- OpenAlex
- W1964574311
- Cited by
- 94
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 8 · 2012: 6
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurotrauma (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG 05-133, P50AG005133)
- National Institute of Neurological Disorders and Stroke (NS-30318, NS07391, T32NS007391)
- 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, IL-1β, traumatic brain injury, controlled cortical impact, amyloid-beta, hippocampus, cerebral cortex, neuroinflammation, Alzheimer's disease
- MeSH terms
- Animals, Brain Injuries, Disease Models, Animal, Immunohistochemistry, Interleukin-1, Peptide Fragments, Time Factors, Blotting, Western, Amyloid beta-Protein Precursor, Rats
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