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Microglial Activation and Chronic Neurodegeneration
Open accessAbstract
Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurodegenerative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (e.g., lipopolysaccharide or neuron damage) or multiple stimuli exposures to result in cumulative neuronal loss with time. Although the mechanisms driving these phenomena are just beginning to be understood, reactive microgliosis (the microglial response to neuron damage) and ROS have been implicated as key mechanisms of chronic and neurotoxic microglial activation, particularly in the case of Parkinson's disease. We review the mechanisms of neurotoxicity associated with chronic microglial activation and discuss the role of neuronal death and microglial ROS driving the chronic and toxic microglial phenotype.
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“MiRNAs can ameliorate degeneration by suppressing microglial activation in the brain and are therefore considered as a therapeutic approach for neurodegenerative diseases (Lull and Block 2010).”
From MiR-124 and MiR-155 as Therapeutic Targets in Microglia-Mediated Inflammation in Multiple Sclerosis (2025) · cites this paper as Lull and Block 2010
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“The notion that neuroinflammatory processes contribute to disease was once provocative, yet recent studies have uncovered multiple mechanisms by which aberrant gliosis causes detrimental neuroinflammation that can influence tau pathology and accelerate neurodegeneration.”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [6]
In the citing paper
“After this acute M1 activation, microglial cells can suffer an uncontrolled activation leading to a state of chronic inflammation. In this state, microglia release neurotoxic inflammatory factors (TNF-α, IL-1α, IL-1β, IL-6, NO, hydrogen peroxide, superoxide anion, chemokines, and glutamate), which lead to neuronal death (Block et al., 2007; Lull and Block, 2010; Burguillos et al., 2011; Kettenmann”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Lull and Block, 2010
In the citing paper
“Neuroinflammation is a characteristic of neurodegenerative diseases, including PD, in which microglia confer pathogenic and exacerbating effects (Lull and Block, 2010; Zhao et al., 2020).”
From Mechanism of miR-132-3p Promoting Neuroinflammation and Dopaminergic Neurodegeneration in Parkinson’s Disease (2022) · cites this paper as Lull and Block, 2010
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Cites
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1 of the 182 references couldn’t be matched to a known paper.
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“Microglia is a chronic source releasing multiple neurotoxic factors including TNF-α, nitric oxide and IL-1β and reactive oxygen species (ROS) which drive neuron damage [65].”
BackgroundCircadian and sleep dysfunction in Alzheimer’s disease
Uddin, M. S., Tewari, D., Mamun, A. A., Kabir, M. T., Niaz, K., Wahed, M. I. I., Barreto, G. E., & Ashraf, G. M. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101046 · Cited by 183
The Effects of Hypoxia and Inflammation on Synaptic Signaling in the CNS
Mukandala, G., Tynan, R., Lanigan, S. M., & O'Connor, J. J. (2016) · Brain Sciences · doi:10.3390/brainsci6010006 · Cited by 176
“The release of TNF-α is a result of the pathogenesis of disorders such as stroke [72], Alzheimer’s disease [73], Parkinson’s disease [74] and severe infections such as meningitis [75], yet its role during hypoxia is not fully understood.”
BackgroundOxidative Stress and Microglial Cells in Parkinson's Disease
Peterson, L. J., & Flood, P. M. (2012) · Mediators of Inflammation · doi:10.1155/2012/401264 · Cited by 167
“The etiology of idiopathic PD now suggests that chronic production of inflammatory mediators by microglial cells, [31, 32, 35], particularly the generation of ROS and NO by activated microglia [23, 33, 34, 36, 37], mediates the majority of DA-neuronal tissue destruction [38].”
BackgroundAnti-Inflammatory Activities of Marine Algae in Neurodegenerative Diseases
Barbalace, M. C., Malaguti, M., Giusti, L., Lucacchini, A., Hrelia, S., & Angeloni, C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20123061 · Cited by 163
“Such chronic inflammatory states result in an abnormal increased cytokine levels [45], the production of neurotoxic mediators, and oxidative stress that triggers a pro-inflammatory cycle [46] and amplifies degenerative processes such as abnormal protein deposition, mitochondrial dysfunction, and BBB permeability impai…”
BackgroundMicroglia and neuronal cell death
Marín‐Teva, J. L., Cuadros, M. Á., Martín‐Oliva, D., & Navascués, J. (2011) · Neuron Glia Biology · doi:10.1017/s1740925x12000014 · Cited by 158
Oksanen, M., Lehtonen, Š., Jaronen, M., Goldsteins, G., Hämäläinen, R. H., & Koıstınaho, J. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03111-7 · Cited by 166
Guo, Y.-W., Hong, W., Wang, X., Zhang, P., Körner, H., Tu, J., & Wei, W. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00125 · Cited by 153
Functional dissection of astrocyte-secreted proteins: Implications in brain health and diseases
Jha, M. K., Kim, J.-H., Song, G. J., Lee, W., Lee, I. K., Lee, H., An, S. S. A., Kim, S., & Suk, K. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.12.003 · Cited by 156
“that suggest that aberrant gliosis is pivotal to the detrimental neuroinflammation that impacts tau pathology and accelerates neurodegeneration (Leyns and Holtzman, 2017; Lull and Block, 2010).”
BackgroundThe immunological response to traumatic brain injury
Needham, E., Helmy, A. E., Zanier, E. R., Jones, J., Coles, A. J., & Menon, D. K. (2019) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2019.04.005 · Cited by 161
Bhandari, R., Paliwal, J. K., & Kuhad, A. (2020) · Advances in neurobiology · doi:10.1007/978-3-030-30402-7_4 · Cited by 167
Mechanical and Biological Interactions of Implants with the Brain and Their Impact on Implant Design
Prodanov, D., & Delbeke, J. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00011 · Cited by 152
“The gap between electrode and functional neurons can thus result from a loss of neurons that have undergone apoptosis (Lull and Block, 2010; Gaudet et al., 2011) or from locally non-functional synapses (Winslow and Tresco, 2010).”
BackgroundHe, J., Zhu, G., Wang, G., & Zhang, F. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/6137521 · Cited by 155
“Considering the dual effects of NOX activation on neurotoxicity and the ubiquity of NOX activation to microglia, it is suggested that NOX in microglia is a key mechanism of neuronal death in a variety of neurodegenerative diseases [93].”
BackgroundPriming of microglia in a DNA-repair deficient model of accelerated aging
Raj, D. D. A., Jaarsma, D., Holtman, I. R., Olah, M., Ferreira, F. M., Schaafsma, W., Brouwer, N., Meijer, M., de Waard, M. C., van der Pluijm, I., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.03.025 · Cited by 147
“Priming of microglia in the aged brain may result from chronic proin fl ammatory cues of the aging environment and is suggested to impair neuronal function and may underlie or promote neurodegeneration (Lull and Block, 2010; Norden and Godbout, 2013; Ransohoff and Perry, 2009).”
Chen, J., Sun, Z., Jin, M., Tu, Y., Wang, S., Yang, X., Chen, Q., Zhang, X., Han, Y., & Pi, R. (2017) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2017.02.010 · Cited by 141
Nanoceria, the versatile nanoparticles: Promising biomedical applications
Saifi, M. A., Seal, S., & Godugu, C. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.08.033 · Cited by 139
Resveratrol and Depression in Animal Models: A Systematic Review of the Biological Mechanisms
Moore, A. C., Beidler, J., & Hong, M. Y. (2018) · Molecules · doi:10.3390/molecules23092197 · Cited by 142
“Overactivation of microglia occurs when neurons are damaged and is associated with several neurodegenerative disorders including depression [42].”
BackgroundThe role of microglia in human disease: therapeutic tool or target?
Cartier, N., Lewis, C. B., Zhang, R., & Rossi, F. M. V. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1330-y · Cited by 142
Cho, H. J., Sajja, V. S. S. S., VandeVord, P. J., & Lee, Y. W. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.08.037 · Cited by 135
Physical activity and exercise attenuate neuroinflammation in neurological diseases
Spielman, L. J., Little, J. P., & Klegeris, A. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.03.012 · Cited by 142
Traumatic Brain Injury and NADPH Oxidase: A Deep Relationship
Angeloni, C., Prata, C., Sega, F. V. D., Piperno, R., & Hrelia, S. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/370312 · Cited by 138
“Given this dual effect of Nox activation on neurotoxicity, the role of Nox in increasing ROS level and the prevalence of Nox activation upon microglial activation suggested that microglial Nox could play a key role in neuronal death after TBI [117].”
BackgroundCathepsin B links oxidative stress to the activation of NLRP3 inflammasome
Bai, H., Yang, B., Yu, W., Xiao, Y. C., Yu, D., & Zhang, Q. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.11.015 · Cited by 138
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
“Analysis of post-mortem brains from both AD and PD patients reveal activated microglia [14], where this microglial activation has been implicated in the progressive nature of each disease [16, 96, 147, 148].”
BackgroundSelf-citationNeuroinflammation, Mast Cells, and Glia: Dangerous Liaisons
Skaper, S. D., Facci, L., Zusso, M., & Giusti, P. (2017) · The Neuroscientist · doi:10.1177/1073858416687249 · Cited by 133
A Tilted Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI
Tapp, Z. M., Godbout, J. P., & Kokiko‐Cochran, O. N. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00345 · Cited by 137
“This population is characterized by increased baseline expression of MhcII and Cd68 and a lower threshold to become hyper-reactive in response to a secondary insult (42).”
BackgroundLangley, M. R., Ghosh, A., Charli, A., Sarkar, S., Ay, M., Luo, J. D., Zielonka, J., Brenza, T. M., Bennett, B., Jin, H., et al. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6905 · Cited by 128
“Reactive mi-crogliosis results from stressed neurons secreting factors that activate microglia, beginning the cycle of neuroinflammation and neuronal damage underlying neurodegenerative diseases (4, 42, 45).”
Jeong, J.-W., Lee, H. H., Han, M. H., Kim, G., Kim, W., & Choi, Y. H. (2014) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2014.01.012 · Cited by 130
Tate, W. P., Walker, M., Sweetman, E., Helliwell, A., Peppercorn, K., Edgar, C. D., Blair, A., & Chatterjee, A. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.877772 · Cited by 131
“Although the mechanism for chronic microglial activation is unclear this evidence clearly shows that a peripheral event could cause a relapse-recovery cycle due to increased BBBP and chronic microglial activation/reactivation with chronic neuroinflammation as a precursor to all of the symptoms of ME/CFS (91).”
BackgroundVacca, V., Marinelli, S., Pieroni, L., Urbani, A., Luvisetto, S., & Pavone, F. (2013) · Pain · doi:10.1016/j.pain.2013.10.027 · Cited by 128
“Astrocytes and microglia are known to play a role in the development, spread, and potentiation of neuropathic pain [21]; they respond to peripheral nerve injury with changes in morphology, proliferation, migration, and expression of inflammatory regulators, activating the phenomenon known as reactive gliosis [33,44,63…”
BackgroundMicroglial activation after ischaemic stroke
Zhang, S. (2019) · Stroke and Vascular Neurology · doi:10.1136/svn-2018-000196 · Cited by 131
Wang, Y., Wu, Y., Li, L., Zheng, J., Liu, R., Zhou, J.-P., Yuan, S., Shang, Y., & Yao, S. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-95 · Cited by 126
“Therefore, inhibiting inflammatory cytokine production by activated microglia may be useful for preventing neurodegeneration [8-10].”
BackgroundMicroglial priming in Alzheimer’s disease
Li, J.-W., Zong, Y., Cao, X.-P., Tan, L., & Tan, L. (2018) · Annals of Translational Medicine · doi:10.21037/atm.2018.04.22 · Cited by 122
“Over time, classical activated microglia (M1) account for a large proportion in all of the microglia and induce an intensive excretion of neurotoxic factors, such as IL-1β, TNF-α, NO and H2O2 (6), and more microglia are primed soon afterwards.”
BackgroundInfluentialProspects for cannabinoid therapies in basal ganglia disorders
Fernández‐Ruíz, J., Moreno‐Martet, M., Rodríguez‐Cueto, C., Palomo‐Garo, C., Gómez‐Cañas, M., Valdeolivas, S., Guaza, C., Romero, J., Guzmán, M., Mechoulam, R., et al. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01365.x · Cited by 127
Badshah, H., Ali, T., Rehman, S. U., Amin, F.-U., Ullah, F., Kim, T. H., & Kim, M. O. (2015) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-015-9623-z · Cited by 125
“Neuroinflammation has been shown to induce neurodegeneration in different forms of brain disorders such as sepsis, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (Gao and Hong 2008; Lull and Block 2010).”
Candiracci, M., Piatti, E., Dominguez-Barragán, M., García-Antrás, D., Rodríguez-Morgado, B., Ruano, D., Gutiérrez, J. F., Parrado, J., & Castaño, A. (2012) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf302468h · Cited by 122
Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration
Jha, S. K., Jha, N. K., Kumar, D., Ambasta, R. K., & Kumar, P. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.06.015 · Cited by 122
Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism
Boontanrart, M. Y., Hall, S. D., Spanier, J. A., Hayes, C. E., & Olson, J. K. (2016) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2016.01.015 · Cited by 123
“Injured neurons release μ-calpain, α-synuclein, and matrix metalloproteinase 3, and neuromelanin which activate microglia toward a pro-inflammatory immune response (Lull and Block, 2010).”
Bagheri, H., Ghasemi, F., Barreto, G. E., Sathyapalan, T., Jamialahmadi, T., & Sahebkar, A. (2019) · BioFactors · doi:10.1002/biof.1597 · Cited by 121
“In addition to this, neuroinflammation attracts other immune cells and can lead to NDs, especially neurodegenerative diseases.(24) Thus, using drugs and compounds that target the pathways in microglia activation is a leading approach to cope with ageing and NDs.”
BackgroundInfluentialKey Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation
Caldeira, C., Cunha, C., Vaz, A. R., Falcão, A. S., Barateiro, A., Seixas, E., Fernandes, A., & Brites, D. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00277 · Cited by 117
“While the ramified morphology relates with the surveilling cell, the amoeboid microglia are associated with activation and believed to favor phagocytosis and mobility (Lull and Block, 2010).”
BackgroundCebrián, C., Loike, J. D., & Sulzer, D. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00114 · Cited by 121
“, 2011, 2013c), and that activated microglia can elicit neurotoxicity (Block et al., 2007; Lull and Block, 2010; Zhao et al., 2013).”
BackgroundYang, Y.-L., Cheng, X., Li, W.-H., Liu, M., Wang, Y.-H., & Du, G.-H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030491 · Cited by 116
“Overactivated microglia cells can produce pro-inflammatory factors, nitric oxide, and reactive oxygen species (ROS), which can damage the BBB and induce neuron damage [14].”
Background
Metadata
- Authors
- Lull, M. E., & Block, M. L.
- Affiliations
- Virginia Commonwealth University (US)
- Corresponding author
- Block, Michelle L.
- Venue
- Neurotherapeutics
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 7
- Issue
- 4
- Pages
- 354-365
- ISSN
- 1878-7479 (ISSN-L)
- PMC
- PMC2951017
- OpenAlex
- W2050320551
- Cited by
- 1,047
- References
- 182
- Citations by year
- 2026: 50 · 2025: 112 · 2024: 94 · 2023: 60 · 2022: 84 · 2021: 95 · 2020: 84 · 2019: 78 · 2018: 83 · 2017: 76 · 2016: 73 · 2015: 43 · 2014: 38 · 2013: 28 · 2012: 30
- FWCI
- 14.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurotherapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Fisher Digital Publications (St. John Fisher College) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences (R01ES016951, R00ES01549)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- microglial activation, neurodegeneration, reactive microgliosis, reactive oxygen species, neuroinflammation, neurotoxicity, Parkinson's disease, neuronal cell death, lipopolysaccharide, TNF-α, nitric oxide, IL-1β
- MeSH terms
- Animals, Chronic Disease, Dopamine, Humans, Models, Biological, Neurons, Oxidation-Reduction, Signal Transduction, Reactive Oxygen Species, Microglia, NADPH Oxidases, Neurodegenerative Diseases
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