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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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Role of Autophagy in HIV-1 and Drug Abuse-Mediated Neuroinflammaging
Sil, S., Thangaraj, A., Oladapo, A., Hu, G., Kutchy, N. A., Liao, K., Buch, S. J., & Periyasamy, P. (2022) · Viruses · doi:10.3390/v15010044 · Cited by 10
Microglial Dyshomeostasis: A Common Substrate in Neurodevelopmental and Neurodegenerative Diseases
Furlan, V. A., MacAuslan, D., Ha, K., Patel, N., Adam, S., Zanagar, B., & Venugopal, S. (2024) · Neuroglia · doi:10.3390/neuroglia5020009 · Cited by 10
“However, it is important to note that the distinction between a homeostatic versus activated state of microglia is complex since microglia can undergo activation as part of normal physiological processes as well [10].”
BackgroundEffect of Capsaicin on 3-NP-Induced Neurotoxicity: A Pre-Clinical Study
Tyagi, S., & Thakur, A. K. (2024) · Neurochemical Research · doi:10.1007/s11064-024-04158-0 · Cited by 10
“Lipo-polysaccharides (LPS) exposure as a strong activator of the microglial cells (innate immune response) [ 27 ] accountable for the induction of neuroinflammation, leads to degenera - tion of neurons [28], especially in HD [29].”
Dietary Anthocyanins Mitigate High-Fat Diet-Induced Hippocampal Inflammation in Mice
Muhammad, I., Cremonini, E., Mathieu, P., Adamo, A. M., & Oteiza, P. I. (2024) · Journal of Nutrition · doi:10.1016/j.tjnut.2024.07.028 · Cited by 10
Kim, N., Choi, H., Kim, U., Kim, S., Kim, Y. B., & Shin, H. Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179451 · Cited by 10
Furan Acids from Nutmeg and Their Neuroprotective and Anti-neuroinflammatory Activities
Le, T. T., Tran, S. H., Lee, S., Kang, S. W., Kim, J. H., Park, K., Kim, C. S., Kim, M., Kang, K., & Jung, S. H. (2025) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5c02528 · Cited by 10
Villacampa, N., Sarlus, H., Martorell, P., Bhalla, K., Castro‐Gomez, S., Vieira-Saecker, A. M. M., Slutzkin, I., Händler, K., Venegas, C., McManus, R. M., et al. (2025) · ASN NEURO · doi:10.1080/17590914.2025.2506406 · Cited by 11
“…activated microglia show enhanced proliferation and cell death together leading to an accelerated turnover of the microglial cell pool (Askew et al., 2017; Doorn et al., 2014; G � omez-Nicola et al., 2013; Hu et al., 2021; Lull & Block, 2010; Ponomarev et al., 2005; Shankaran et al., 2007).”
Neurotoxicity of air pollution: Role of neuroinflammation
Costa, L. G., Cole, T. B., Dao, K., Chang, Y. C., Coburn, J. L., & Garrick, J. M. (2018) · Advances in neurotoxicology · doi:10.1016/bs.ant.2018.10.007 · Cited by 11
del Campo, M., Fernández‐Calle, R., Vicente‐Rodríguez, M., Martínez, S. M., Gramage, E., Zapico, J. M., Haro, M., & Herradón, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136646 · Cited by 10
“Indeed, microglia can be activated by various stimuli including neuronal injury [4], which is an important mechanism involved in PD pathogenesis [28].”
BackgroundPotential repositioning of exemestane as a neuroprotective agent for Parkinson’s disease
Son, H. J., Han, S. H., Lee, J. A., Shin, E. J., & Hwang, O. (2017) · Free Radical Research · doi:10.1080/10715762.2017.1353688 · Cited by 10
“Furthermore, ROS induces production of the inflammatory mediators such as nitric oxide (NO), superoxide, interleukin-1b (IL-1b), and tumour necrosis factor-a (TNF-a) in microglia, all of which can cause damage to nearby neurons [2].”
BackgroundIso-α-Acids, the Bitter Components of Beer, Suppress Microglial Inflammation in rTg4510 Tauopathy
Ano, Y., Takaichi, Y., Uchida, K., Kondô, K., Nakayama, H., & Takashima, A. (2018) · Molecules · doi:10.3390/molecules23123133 · Cited by 10
“including reactive oxygen spices and inflammatory cytokines [21].”
BackgroundWang, J., Liu, Y., Liu, Y., Zhu, K., & Xie, A. (2020) · Neuroscience Letters · doi:10.1016/j.neulet.2020.135005 · Cited by 10
Neuroinflammation and neuropathology
Esin, R. G., SAFINA, D. R., Раисовна, Х. А., & Esin, O. R. (2021) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro2021121041107 · Cited by 13
Kalgudi, S., & Ho, K. M. (2020) · Neurocritical Care · doi:10.1007/s12028-020-01026-x · Cited by 10
Nematullah, M., Rashid, F., Nimker, S., & Khan, F. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03324-9 · Cited by 9
Vision loss associated with silicone oil endotamponade in vitreoretinal surgery – a review
Januschowski, K., Rickmann, A., Smith, J. M., Pastor‐Idoate, S., & Jimeno, J. C. P. (2024) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-024-06520-y · Cited by 9
“Even more, chronic microglial activation is implicated in the mechanisms of neurotoxicity [73] and it has been demonstrated that emulsified silicone oil changes the activity level of retinal microglia [74].”
Irisin Attenuates Neuroinflammation Targeting the NLRP3 Inflammasome
Filannino, F. M., Ruggiero, M., Panaro, M. A., Lofrumento, D. D., Trotta, T., Benameur, T., Cianciulli, A., Calvello, R., Zoila, F., & Porro, C. (2024) · Molecules · doi:10.3390/molecules29235623 · Cited by 10
Yang, H., Gao, J., Wang, H., Ma, X.-M., Liu, B.-Y., Song, Q. Y., Cheng, H., Li, S., Long, Z.-Y., Lu, X., et al. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149392 · Cited by 9
Chunowski, P., Otto‐Ślusarczyk, D., Duszyńska-Wąs, K., Drzewińska, A., Załęski, A., Madetko‐Alster, N., Wiercińska‐Drapało, A., Struga, M., & Alster, P. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252313211 · Cited by 9
Campos, G. S.-G., Zafra, Á. M., Rodríguez, M. E., Cordones, I., Ruffini, G., & Márquez‐Ruiz, J. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1549230 · Cited by 9
“Rather, the relationship between pathology clearance and neuroinflammation is complex, as microglial activation states can be both a consequence and a modulator of disease pathology (Lull and Block, 2010; Hansen et al., 2018).”
Piezo1 in microglial cells: Implications for neuroinflammation and tumorigenesis
Yang, B., Li, Z., Li, P., Liu, Y., Ding, X., & Feng, E. (2025) · Channels · doi:10.1080/19336950.2025.2492161 · Cited by 9
“…wrap Aβ plaques, and their long-term activation can lead to reactive microgliosis, creating a vicious cycle that accelerates neurodegeneration [92,93]: while neuroinflammation initially serves as a protective mechanism to clear debris and pathogens, its chronic activation in AD contributes to…”
Regional Molecular Changes in Chronic Lipopolysaccharide-Induced Neuroinflammation
Pienaar, L., Ramsamy, A., Millen, A. M. E., & Baijnath, S. (2025) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2025.100515 · Cited by 10
Singh, A. K., Dhalayat, K., Dhobale, S. V., Ghosh, B., Datta, A., Borah, A., & Bhattacharya, P. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102780 · Cited by 9
TREM2 inhibits LPS-induced pyroptosis and inflammation by promoting mitophagy via SYK in BV2 cells
Jiang, W., Fan, X., Wu, H., Song, J., Yang, C., & Zhao, Z. (2025) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2025.107500 · Cited by 10
Chauhan, P., Wadhwa, K., & Singh, G. (2025) · Pathology - Research and Practice · doi:10.1016/j.prp.2025.156109 · Cited by 12
Cha, J., Raj, D., Choi, K. S., Rajendra, J. K., Nemeroff, C. B., Felger, J. C., Craighead, W. E., Mayberg, H. S., & Dunlop, B. W. (2025) · Biological Psychiatry · doi:10.1016/j.biopsych.2025.06.026 · Cited by 12
Song, P., Yi, Z., Fu, Y., Song, D., Chen, K., Zheng, J., Sun, Y.-J., & Diao, Y. (2021) · Journal of Healthcare Engineering · doi:10.1155/2021/3048383 · Cited by 9
“MI typically reside in a resting state but are rapidly activated when the CNS is stressed, a process called MI activation [10].”
BackgroundRetractedMonocytes maintain central nervous system homeostasis following helminth-induced inflammation
Jianya, P., Sy, C. B., Ponessa, J. J., Lemenze, A. D., Hernandez, C. M., Inclan-Rico, J. M., Sawhney, A., Federman, H. G., Chavan, K., Espinosa, V., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2201645119 · Cited by 9
Parkinson's Disease Progression and Exposure to Contaminated Water at Camp Lejeune
Goldman, S. M., Weaver, F. M., González, B., Stroupe, K. T., Cao, L., Colletta, K., Brown, E. G., & Tanner, C. M. (2024) · Movement Disorders · doi:10.1002/mds.29922 · Cited by 10
“55,56 Indeed, persistent microglial activation and active nigral neuronal degeneration was observed in monkey models and at autopsy in persons exposed to the parkinsonism-inducing-toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine many years earlier.”
Blewett, N. H., Iben, J., Gaidamakov, S., & Maraia, R. J. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00588-16 · Cited by 10
“cases, astrocyte activation can be chronic and can contribute to pathogenesis (121).”
BackgroundRhes Counteracts Dopamine Neuron Degeneration and Neuroinflammation Depending on Gender and Age
Costa, G., Pinna, A., Porceddu, P. F., Casu, M. A., Maio, A. D., Napolitano, F., Usiello, A., & Morelli, M. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00163 · Cited by 9
Role of PUMA in the methamphetamine-induced migration of microglia
Zhao, L., Du, L., Zhang, Y., Chao, J., Duan, M., Yao, H., Shen, C., & Zhang, Y. (2018) · Metabolic Brain Disease · doi:10.1007/s11011-018-0319-y · Cited by 9
Characterization of aged male BALB/ccenp mice as a model of dementia
Esquivel, N., García, Y., Lores, B., Gutiérrez, M., & Martínez, C. R. (2020) · Laboratory Animal Research · doi:10.1186/s42826-020-00038-0 · Cited by 9
Wang, Y., Meagher, R. B., Ambati, S., Ma, P., & Phillips, B. G. (2020) · Sleep And Breathing · doi:10.1007/s11325-020-02205-y · Cited by 9
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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