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Progressive Neurodegeneration After Experimental Brain Trauma: Association With Chronic Microglial Activation
Open accessAbstract
Recent clinical studies indicate that traumatic brain injury (TBI) produces chronic and progressive neurodegenerative changes leading to late neurologic dysfunction, but little is known about the mechanisms underlying such changes. Microglial-mediated neuroinflammationis an important secondary injury mechanism after TBI. In human studies, microglial activation has been found to persist for many years after the initial brain trauma, particularly after moderate to severe TBI. In the present study, adult C57Bl/6 mice were subjected to single moderate-level controlled cortical impact and were followed up by longitudinal T2-weighted magnetic resonance imaging in combination with stereologic histologic assessment of lesion volume expansion, neuronal loss, and microglial activation for up to 1 year after TBI. Persistent microglial activation was observed in the injured cortex through 1 year after injury and was associated with progressive lesion expansion, hippocampal neurodegeneration, and loss of myelin. Notably, highly activated microglia that expressed major histocompatibility complex class II (CR3/43), CD68, and NADPH oxidase (NOX2) were detected at the margins of the expanding lesion at 1 year after injury; biochemical markers of neuroinflammation and oxidative stress were significantly elevated at this time point. These data support emerging clinical TBI findings and provide a mechanistic link between TBI-induced chronic microglial activation and progressive neurodegeneration.
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“In the minutes following TBI, microglia are recruited via purinergic signaling to clear necrotic debris and adopt a phagocytic state [100,107,108].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [100]
In the citing paper
“TBI is a biphasic injury: after the mechanical primary injury, a secondary dystrophic state produces long-term dysfunction in the brain that includes elevated neuroinflammation as a result of blood-brain barrier disruption, increased oxidative stress, and persistent changes in the microglial population [100–106].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [100]
In the citing paper
“Of recent interest is how post-injury microglia promote increased oxidative damage leading to neurodegeneration through a NOX2-dependent mechanism [100,117,118].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [100]
In the citing paper
“Microglia associated with the long-term inflammatory phenotype following TBI are commonly defined as MHC-II/CD86/Cd11b positive, with upregulated expression of NOX24, Tlr4, Trem2, CD68, Clec7a, and Stat1, and higher expression of interferon- and immune-associated signaling genes [100,112,115,116].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [100]
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Citations
Cites
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Block, M. L., Zecca, L., & Hong, J.-S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2038 · Cited by 4,110
ATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913
Kigerl, K. A., Gensel, J. C., Ankeny, D. P., Alexander, J. K., Donnelly, D. J., & Popovich, P. G. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3257-09.2009 · Cited by 2,130
Hu, X., Li, P., Guo, Y., Wang, H., Leak, R. K., Chen, S., Gao, Y., & Chen, J. (2012) · Stroke · doi:10.1161/strokeaha.112.659656 · Cited by 1,573
Microglia in neurodegenerative disease
Perry, V. H., Nicoll, J. A. R., & Holmes, C. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.17 · Cited by 1,543
The P2Y12 receptor regulates microglial activation by extracellular nucleotides
Haynes, S. E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M. E., Gan, W.-B., & Julius, D. (2006) · Nature Neuroscience · doi:10.1038/nn1805 · Cited by 1,542
Microglial Activation and Chronic Neurodegeneration
Lull, M. E., & Block, M. L. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.05.014 · Cited by 1,047 · cited 2×
“In this study, we show that NADPH oxidase is chronically expressed in highly activated microglia surrounding the lesion site at 1 year after injury, and that its activity may be a key driver of self-propagating cycles of microglial-mediated neurodegeneration, as in other models of chronic neurodegenerative diseases (3…”
BackgroundInflammation and white matter degeneration persist for years after a single traumatic brain injury
Johnson, V. E., Stewart, J. E., Begbie, F. D., Trojanowski, J. Q., Smith, D. H., & Stewart, W. (2013) · Brain · doi:10.1093/brain/aws322 · Cited by 1,045
Inflammation after trauma: Microglial activation and traumatic brain injury
Ramlackhansingh, A. F., Brooks, D. J., Greenwood, R. J., Bose, S. K., Turkheimer, F. E., Kinnunen, K. M., Gentleman, S., Heckemann, R. A., Gunanayagam, K., Gelosa, G., et al. (2011) · Annals of Neurology · doi:10.1002/ana.22455 · Cited by 999
Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain
Colton, C. A. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9164-4 · Cited by 916
Neuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention
Kumar, A., & Loane, D. J. (2012) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2012.06.008 · Cited by 710
Self-citationWu, D., Teismann, P., Tieu, K., Vila, M., Jackson-Lewis, V. R., Ischiropoulos, H., & Przedborski, S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0937239100 · Cited by 634
Qin, L., Liu, Y., Wang, T., Wei, S.-J., Block, M. L., Wilson, B., Liu, B., & Hong, J.-S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m307657200 · Cited by 574
Loane, D. J., & Faden, A. I. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.09.005 · Cited by 574
Self-citationTranslocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repair
Chen, M.-K., & Guilarte, T. R. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2007.12.004 · Cited by 506
Progressive atrophy and neuron death for one year following brain trauma in the rat
Smith, D. H., Chen, X.-H., Pierce, J. E. S., Wolf, J. A., Trojanowski, J. Q., Graham, D. I., & McIntosh, T. K. (1997) · Journal of Neurotrauma · doi:10.1089/neu.1997.14.715 · Cited by 440
Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS
Liao, B., Zhao, W., Beers, D. R., Henkel-Tigges, J., & Appel, S. H. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.06.011 · Cited by 438
Redox regulation of glial inflammatory response to lipopolysaccharide and interferonγ
Pawate, S., Shen, Q., Fan, F., & Bhat, N. R. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20180 · Cited by 428
Pierce, J. E. S., Smith, D. H., Trojanowski, J. Q., & McIntosh, T. K. (1998) · Neuroscience · doi:10.1016/s0306-4522(98)00142-0 · Cited by 385
Bendlin, B. B., Ries, M. L., Lazar, M., Alexander, A. L., Dempsey, R. J., Rowley, H. A., Sherman, J. E., & Johnson, S. C. (2008) · NeuroImage · doi:10.1016/j.neuroimage.2008.04.254 · Cited by 339
Fox, G. B., Fan, L., LeVasseur, R. A., & Faden, A. I. (1998) · Journal of Neurotrauma · doi:10.1089/neu.1998.15.599 · Cited by 320
Self-citationMcMillan, T. M., Teasdale, G. M., & Stewart, E. (2012) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2012-302746 · Cited by 315 · cited 1×
“In a prospective cohort of more than 200 TBI survivors followed for up to 12 to 14 years, neurobehavioral disability worsened over time in a significant number (25).”
BackgroundDixon, C. E., Kochanek, P. M., Yan, H. Q., Schiding, J. K., GRIFFITH, R. G., Baum, E., Marion, D. W., & DeKosky, S. T. (1999) · Journal of Neurotrauma · doi:10.1089/neu.1999.16.109 · Cited by 303
Activation of NADPH Oxidase in Alzheimer’s Disease Brains
Shimohama, S., Tanino, H., Kawakami, N., Okamura, N., Kodama, H., Yamaguchi, T., Hayakawa, T., Nunomura, A., Chiba, S., Perry, G., et al. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2897 · Cited by 292
Inhibition of NADPH Oxidase is Neuroprotective after Ischemia—Reperfusion
Chen, H., Song, Y. S., & Chan, P. H. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.47 · Cited by 291
Long-term intracerebral inflammatory response after traumatic brain injury
Gentleman, S. M., Leclercq, P. D., Moyes, L., Graham, D. I., Smith, C., Griffin, W. S. T., & Nicoll, J. A. R. (2004) · Forensic Science International · doi:10.1016/j.forsciint.2004.06.027 · Cited by 272
Qin, L., Liu, Y., Hong, J., & Crews, F. T. (2013) · Glia · doi:10.1002/glia.22479 · Cited by 271
The multifaceted profile of activated microglia
Lynch, M. A. (2009) · Molecular Neurobiology · doi:10.1007/s12035-009-8077-9 · Cited by 268
Neuroinflammation – An Early Event in Both the History and Pathogenesis of Alzheimer’s Disease
Eikelenboom, P., van Exel, E. R., Hoozemans, J. J. M., Veerhuis, R., Rozemüller, A. J. M., & van Gool, W. A. (2010) · Neurodegenerative Diseases · doi:10.1159/000283480 · Cited by 259
Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury
Loane, D. J., Pocivavsek, A., Moussa, C. E.-H., Thompson, R., Matsuoka, Y., Faden, A. I., Rebeck, G. W., & Burns, M. P. (2009) · Nature Medicine · doi:10.1038/nm.1940 · Cited by 246
Self-citationKumar, A., Stoica, B. A., Sabirzhanov, B., Burns, M. P., Faden, A. I., & Loane, D. J. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.013 · Cited by 244
Self-citationMander, P. K., & Brown, G. C. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-20 · Cited by 229
The neuroinflammatory response in humans after traumatic brain injury
Smith, C., Gentleman, S. M., Leclercq, P. D., Murray, L. S., Griffin, W. S. T., Graham, D. I., & Nicoll, J. A. R. (2012) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12008 · Cited by 213
Zhang, Q.-G., Laird, M. D., Han, D., Nguyen, K., Scott, E., Dong, Y., Dhandapani, K. M., & Brann, D. W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034504 · Cited by 211
Acosta, S. A., Tajiri, N., Shinozuka, K., Ishikawa, H., Grimmig, B. A., Diamond, D. M., Sanberg, P. R., Bickford, P. C., Kaneko, Y., & Borlongan, C. V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053376 · Cited by 201
Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury
Dohi, K., Ohtaki, H., Nakamachi, T., Yofu, S., Satoh, K., Miyamoto, K., Song, D., Tsunawaki, S., Shioda, S., & Aruga, T. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-41 · Cited by 188
Late exercise reduces neuroinflammation and cognitive dysfunction after traumatic brain injury
Piao, C.-S., Stoica, B. A., Wu, J., Sabirzhanov, B. E., Zhao, Z., Cabatbat, R. M., Loane, D. J., & Faden, A. I. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.12.017 · Cited by 178
Self-citationProlonged Activation of NF-κB Following Traumatic Brain Injury in Rats
NONAKA, M., CHEN, X.-H., PIERCE, J. E. S., LEONI, M. J., McINTOSH, T. K., WOLF, J. A., & SMITH, D. H. (1999) · Journal of Neurotrauma · doi:10.1089/neu.1999.16.1023 · Cited by 176
Byrnes, K. R., Loane, D. J., Stoica, B. A., Zhang, J., & Faden, A. I. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-43 · Cited by 175
Self-citationProlonged Microgliosis in the Rhesus Monkey Central Nervous System after Traumatic Brain Injury
Nagamoto-Combs, K., McNeal, D. W., Morecraft, R. J., & Combs, C. K. (2007) · Journal of Neurotrauma · doi:10.1089/neu.2007.0377 · Cited by 156
Targeting microglia-mediated neurotoxicity: the potential of NOX2 inhibitors
Surace, M. J., & Block, M. L. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1015-4 · Cited by 134
NADPH oxidase is involved in post-ischemic brain inflammation
Chen, H., Kim, G. S., Okami, N., Narasimhan, P., & Chan, P. H. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.01.027 · Cited by 117
Longitudinal Volumetric Changes following Traumatic Brain Injury: A Tensor-Based Morphometry Study
Farbota, K. D. M., Sodhi, A., Bendlin, B. B., McLaren, D. G., Xu, G., Rowley, H. A., & Johnson, S. C. (2012) · Journal of the International Neuropsychological Society · doi:10.1017/s1355617712000835 · Cited by 104
NOX Activity Is Increased in Mild Cognitive Impairment
Bruce‐Keller, A. J., Gupta, S., Parrino, T. E., Knight, A. G., Ebenezer, P. J., Weidner, A. M., LeVine, H., Keller, J. N., & Markesbery, W. R. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2823 · Cited by 101
Ng, K., Mikulis, D., Glazer, J., Kabani, N., Till, C., Greenberg, G., Thompson, A., Lazinski, D., Agid, R., Colella, B., et al. (2008) · Archives of Physical Medicine and Rehabilitation · doi:10.1016/j.apmr.2008.07.006 · Cited by 101
Long-term intracerebral inflammatory response after experimental focal brain injury in rat
Holmin, S., & Mathiesen, T. I. (1999) · Neuroreport · doi:10.1097/00001756-199906230-00017 · Cited by 98
Kabadi, S. V., Stoica, B. A., Byrnes, K. R., Hanscom, M., Loane, D. J., & Faden, A. I. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2011.117 · Cited by 96
Self-citationChung, W., Chang, A. C., Kato, I., & Chang, N.-C. A. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.72.1.72 · Cited by 88
Emerging roles for telomerase in neuronal development and apoptosis
Mattson, M. P., & Klapper, W. (2001) · Journal of Neuroscience Research · doi:10.1002/1097-4547(20010101)63:1 · Cited by 76
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DiSabato, D. J., Quan, N., & Godbout, J. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13607 · Cited by 1,640
The far-reaching scope of neuroinflammation after traumatic brain injury
Simon, D. W., McGeachy, M. J., Bayır, H., Clark, R. S. B., Loane, D. J., & Kochanek, P. M. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.13 · Cited by 1,190
Self-citationThe neuropathology of traumatic brain injury
McKee, A. C., & Daneshvar, D. H. (2015) · Handbook of clinical neurology · doi:10.1016/b978-0-444-52892-6.00004-0 · Cited by 899
Microglia in the TBI brain: The good, the bad, and the dysregulated
Loane, D. J., & Kumar, A. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.08.018 · Cited by 850
Self-citationNeuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift
Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B., & El Khoury, J. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.010 · Cited by 799
Metadata
- Authors
- Loane, D. J., Kumar, A., Stoica, B. A., Cabatbat, R., & Faden, A. I.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Loane, David J.
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-01
- Volume
- 73
- Issue
- 1
- Pages
- 14-29
- ISSN
- 0022-3069 (ISSN-L)
- PMC
- PMC4267248
- OpenAlex
- W2067451082
- Cited by
- 498
- References
- 49
- Citations by year
- 2026: 35 · 2025: 28 · 2024: 42 · 2023: 39 · 2022: 39 · 2021: 68 · 2020: 56 · 2019: 42 · 2018: 36 · 2017: 41 · 2016: 31 · 2015: 24 · 2014: 17
- FWCI
- 15.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS037313, R01NS052568, R01NS082308)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- traumatic brain injury, progressive neurodegeneration, microglial activation, neuroinflammation, controlled cortical impact, lesion expansion, hippocampal neurodegeneration, demyelination, oxidative stress, NADPH oxidase, CD68
- MeSH terms
- Animals, Brain Injuries, Disease Models, Animal, Male, Mice, Inbred C57BL, Time Factors, Microglia, Disease Progression, Neurodegenerative Diseases, Mice
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