The DOI matches its Crossref record; 181 of the 182 references it cites were found in a registry or an index.
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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BackgroundAre dopamine derivatives implicated in the pathogenesis of Parkinson's disease?
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Mahbub, N. U., Islam, M. M., Hong, S., & Chung, H. (2024) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2024.1348279 · Cited by 90
“Neuronal damage can initiate a process known as reactive microgliosis, ultimately resulting in the progressive degeneration of dopaminergic neurons (Tansey et al., 2007; Lull and Block, 2010).”
BackgroundJeon, M.-T., Kim, K.-S., Kim, E. S., Lee, S., Kim, J., Hoe, H.-S., & Kim, D.-G. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101333 · Cited by 76
“may contribute to neuroinflammation-mediated neurodegeneration (Kim and Joh, 2006; Lee and MacLean, 2015; Lull and Block, 2010).”
Methamphetamine induced neurotoxic diseases, molecular mechanism, and current treatment strategies
Shrestha, P., Katila, N., Lee, S., Seo, J. H., Jeong, J., & Yook, S. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113591 · Cited by 91
Kim, M. E., & Lee, J. S. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb47010008 · Cited by 82
“They also release reactive oxygen species (ROS) and nitric oxide (NO), further exacerbating oxidative stress and neuronal damage [3,19].”
Targeting NOX enzymes in the central nervous system: therapeutic opportunities
Sorce, S., Krause, K., & Jaquet, V. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1014-5 · Cited by 79
“As a major source of ROS, NOX2 can induce direct neuronal damage [128] and maintain microglial cells in an activated stage where they produce neurotoxic molecules like peroxynitrite and other inflammatory molecules [94].”
BackgroundExpression of Inducible Nitric Oxide Synthase (iNOS) in Microglia of the Developing Quail Retina
Sierra, A., Navascués, J., Cuadros, M. Á., Calvente, R., Martín‐Oliva, D., Ferrer‐Martín, R. M., Martín‐Estebané, M., Carrasco, M., & Marín‐Teva, J. L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106048 · Cited by 78
Sekar, P., Huang, D.-Y., Hsieh, S.-L. E., Chang, S., & Lin, W. (2018) · Cell Communication and Signaling · doi:10.1186/s12964-018-0293-3 · Cited by 82
Macrophages in the cochlea; an immunological link between risk factors and progressive hearing loss
Hough, K., Verschuur, C. A., Cunningham, C. M., & Newman, T. A. (2021) · Glia · doi:10.1002/glia.24095 · Cited by 76
“Primed microglia typically show greater expression of inflammatory markers coupled with a lower threshold to switch to a pro-inflammatory state (Lull & Block, 2010).”
BackgroundEffect of Systemic Inflammation in the CNS: A Silent History of Neuronal Damage
Solano, M. V. M., Lara, C. S., Sánchez-Garibay, C., Soto-Rojas, L. O., Escobedo-Ávila, I., Tena‐Suck, M. L., Ortiz-Butrón, R., Choreño-Parra, J. A., Romero‐López, J. P., & Meléndez-Camargo, M. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241511902 · Cited by 78
Ye, J., Jiang, Z., Chen, X., Liu, M., Li, J., & Liu, N. (2015) · Experimental Cell Research · doi:10.1016/j.yexcr.2015.10.026 · Cited by 76
Turchan-Cholewo, J. T., Smith, V. D., Gupta, S., Gorospe, R. M. C., Keller, J. N., & Bruce‐Keller, A. J. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2097 · Cited by 78
The Neuroinflammatory Response in ALS: The Roles of Microglia and T Cells
Lewis, C.-A., Manning, J., Rossi, F., & Krieger, C. (2012) · Neurology Research International · doi:10.1155/2012/803701 · Cited by 76
“(MHCs), and are poor antigen presenting cells (APCs; [14]).”
BackgroundZhao, Q., Li, J., Feng, J., Wang, X., Liu, Y., Wang, F., Liu, L., Jin, B., Lin, M. S., Wang, Y., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01379-7 · Cited by 86
“This prolonged activation resembles microglial responses observed in neurodegenerative diseases such as Alzheimer’s disease and Huntington’s disease, in which chronic neuroinflammation exacerbates neuronal dysfunction 32–34 .”
Borrajo, A., Rodriguez-Perez, A. I., Villar-Cheda, B., Guerra, M. J., & Labandeira-Garcia, J. L. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.05.021 · Cited by 75
Puttachary, S., Sharma, S., Verma, S., Yang, Y., Putra, M. R. E., Thippeswamy, A., Luo, D., & Thippeswamy, T. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.05.013 · Cited by 75
Influence of Estrogen Modulation on Glia Activation in a Murine Model of Parkinson's Disease
Siani, F., Greco, R., Levandis, G., Ghezzi, C., Daviddi, F., Demartini, C., Vegeto, E., Armentero, M., & Blandini, F. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00306 · Cited by 77
“…but a chronic reactivity of these cells concur to the release of different cytotoxic molecules, such as reactive oxygen species, chemokines and pro-inflammatory cytokines (Su and Federoff, 2014), which play a pivotal role in PD neurodegeneration (Lull and Block, 2010; Perego et al., 2011).”
BackgroundInfluentialFloridoside suppresses pro-inflammatory responses by blocking MAPK signaling in activated microglia
Kim, M., Li, Y.-X., Dewapriya, P., Ryu, B., & Kim, S. (2013) · BMB Reports · doi:10.5483/bmbrep.2013.46.8.237 · Cited by 75
Insulin resistance, neuroinflammation, and Alzheimer’s disease
Najem, D., Bamji‐Mirza, M., Chang, N., Liu, Q. Y., & Zhang, W. (2014) · Reviews in the Neurosciences · doi:10.1515/revneuro-2013-0050 · Cited by 76
Endocytotic uptake of iron oxide nanoparticles by cultured brain microglial cells
Luther, E. M., Petters, C., Bulcke, F., Kaltz, A., Thiel, K., Bickmeyer, U., & Dringen, R. (2013) · Acta Biomaterialia · doi:10.1016/j.actbio.2013.05.022 · Cited by 73
“However, upon activation by brain injury or infections, microglial cells migrate to the site of the impact and secrete inflammatory proteins and reactive oxygen species (ROS) that may damage neighbouring cells [7,9].”
BackgroundKaewmool, C., Kongtawelert, P., Phitak, T., Pothacharoen, P., & Udomruk, S. (2020) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2020.577164 · Cited by 75
Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy
Simó, R., Simó‐Servat, O., Bogdanov, P. M., & Hernández, C. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13081320 · Cited by 77
Leonoudakis, D., Rane, A., Angeli, S., Lithgow, G. J., Andersen, J. K., & Chinta, S. J. (2017) · Mediators of Inflammation · doi:10.1155/2017/8302636 · Cited by 72
Gonadal hormones and the control of reactive gliosis
Arévalo, M., Santos‐Galindo, M., Acaz‐Fonseca, E., Azcoitia, Í., & García‐Segura, L. M. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.02.021 · Cited by 74
“neuronal damage and amplify the neurodegenerative process (Sofroniew, 2009; Graeber and Streit, 2010; Lull and Block, 2010).”
Russo, I., Kaganovich, A., Ding, J., Landeck, N., Mamais, A., Varanita, T., Biosa, A., Tessari, I., Bubacco, L., Greggio, E., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.05.012 · Cited by 68
Ferrari, G., Bignami, F., Giacomini, C., Capitolo, E., Comi, G., Chaabane, L., & Rama, P. (2014) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-13984 · Cited by 71
Martín, R., Hernández, M., Córdova, C., & Nieto, M. L. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01869.x · Cited by 71
“Several ischaemic and neurodegenerative disorders are associated with proliferation and overactivation of microglia (Lull and Block, 2010).”
BackgroundTREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42 in HMC3 cells
Akhter, R., Shao, Y., Formica, S., Khrestian, M., & Bekris, L. M. (2021) · Molecular Immunology · doi:10.1016/j.molimm.2020.12.035 · Cited by 68
Lo, J. Y., Kamarudin, M. N. A., Hamdi, O. A. A., Awang, K., & Kadir, H. A. (2015) · Food & Function · doi:10.1039/c5fo00607d · Cited by 71
Kallaur, A. P., Reiche, E. M. V., Oliveira, S. R., Simão, A. N. C., Pereira, W. L. D. C. J., Alfieri, D. F., Flauzino, T., Proença, C. D. M., Lozovoy, M. A. B., Kaimen-Maciel, D. R., et al. (2016) · Molecular Neurobiology · doi:10.1007/s12035-015-9648-6 · Cited by 75
“Following immune and oxidative damage, the neurons may release microglial activators, including matrix metalloproteinase 3, α-synuclein, and neuromelanin, which may cause a self-perpetuating cycle of neurotoxicity known as reactive microgliosis [90].”
BackgroundKesler, S. R., Gugel, M., Huston-Warren, E., & Watson, C. (2016) · Brain Connectivity · doi:10.1089/brain.2015.0409 · Cited by 71
“Methotrexatemayalsoincreasemicroglialactivation (Seigersetal.,2010;Woodetal.,2014),whichisassociated withseveralneurotoxiceffects,includingoxidativeandnitro-sativestress(LullandBlock,2010).”
Hossain, M. M., Liu, J., & Richardson, J. R. (2016) · Toxicological Sciences · doi:10.1093/toxsci/kfw187 · Cited by 68
Wang, J.-W., Chen, S.-D., Zhang, X.-L., & Jonas, J. B. (2016) · Journal of Glaucoma · doi:10.1097/ijg.0000000000000200 · Cited by 69
3D tissue engineering, an emerging technique for pharmaceutical research
Jensen, G., Morrill, C. C., & Huang, Y. (2018) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2018.03.006 · Cited by 68
“Unregulated and prolonged activation of these immune cells may contribute to the self-propelling nature of neurodegenerative diseases 3,13 – 16 .”
Elucidating the Neuropathologic Mechanisms of SARS-CoV-2 Infection
Pacheco‐Herrero, M., Soto-Rojas, L. O., Harrington, C. R., Flores-Martinez, Y. M., Villegas-Rojas, M. M., León-Aguilar, A. M., Martínez-Gómez, P. A., Campa-Córdoba, B. B., Apátiga-Pérez, R., Corniel-Taveras, C. N., et al. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.660087 · Cited by 71
Fachel, F. N. S., Schuh, R. S., Veras, K. S., Bassani, V. L., Koester, L., Henriques, A. T., Braganhol, E., & Teixeira, H. F. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.11.003 · Cited by 72
“This condition is especially relevant in ND due to the prolonged progression of these diseases, in which chronic neuronal damage and protein aggregates are associated with constant activation of the microglial immune-inflammatory system (Cunningham et al., 2009; Fischer and Maier, 2015; Lull and Block, 2010; Wang et a…”
Alzheimer's disease: Innate immunity gone awry?
VanItallie, T. B. (2017) · Metabolism · doi:10.1016/j.metabol.2017.01.014 · Cited by 67
Microglial LOX-1 reacts with extracellular HSP60 to bridge neuroinflammation and neurotoxicity
Zhang, D., Sun, L., Zhu, H., Wang, L., Wu, W., Xie, J., & Gu, J. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.07.019 · Cited by 67
Neuromodulation of Glial Function During Neurodegeneration
Stevenson, R., Samokhina, E., Rossetti, I., Morley, J. W., & Buskila, Y. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00278 · Cited by 72
Prowse, N. A., & Hayley, S. P. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.09.018 · Cited by 72
“Certainly, microglial inflammatory processes have been well studied, and in the worst possible scenario, this can result in massive tissue loss and degeneration of the CNS (Lull and Block, 2010), with microglia increasingly implicated in the pathologies of Parkinson’s disease (PD) and Alzheimer’s disease (Bartels et a…”
Influential
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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