Cited by 1,047Neuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and TreatmentsInflammasome and immune disorders

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Microglial Activation and Chronic Neurodegeneration

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Lull, Melinda E., Block, Michelle L.·2010·Neurotherapeutics

DOI 10.1016/j.nurt.2010.05.014PMC PMC2951017

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Abstract

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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Background
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Result
Amount of Mononuclear Phagocyte Infiltrate Does Not Predict Area of Experimental Choroidal Neovascularization (CNV)
Will-Orrego, A., Qiu, Y., Fassbender, E. S., Shen, S., Aranda, J., Kotagiri, N., Maker, M., Liao, S.-M., JAFFEE, B. D., & Poor, S. H. (2018) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2017.0131 · Cited by 6
“With chronic activation, microglia release excessive inflammatory and angiogenic factors that cause both neuronal and RPE degeneration.(13,14) Factors contributing to chronic retinal microglia activation include aging, pro-inflammatory cytokines, complement activation products, lipofuscin, oxidized lipid deposits, and…”
Natural Inhibitors on Over-Activation of Microglia from Herbals
Bai, Z., Chen, G., Li, W., Hou, Y., & Li, N. (2019) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.c18-00926 · Cited by 6
Involvement of lncRNAs NEAT1 and ZBTB11-AS1 in Active and Persistent HIV-1 Infection in C20 Human Microglial Cell Line
Pereira-Montecinos, C., Pittet-Díaz, I., Morales-Vejar, I., Millán-Hidalgo, C., Rojas-Celis, V., Vallejos‐Vidal, E., Reyes‐López, F. E., Fuenzalida, L., Reyes-Cerpa, S., & Toro‐Ascuy, D. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26104745 · Cited by 5
“Recent evidence suggests that microglia can undergo all three stages of infection [15–17]; however, the molecular mechanisms governing the establishment and regulation of active, persistent, and latent HIV-1 infections in microglia remain an area of significant research.”
Sex differences in inflammatory mechanisms related to alcohol use disorder and depression
Ramirez, E. B. D., & Schank, J. R. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.106172 · Cited by 5
Neurodevelopmental origins of neurodegeneration: a lifespan perspective on brain vulnerability
Kopalli, S. R., Vadia, N., Varma, P., Mishra, S., Joshi, N., Bansal, P., Al-Hasnaawei, S., Chauhan, A. S., Jain, H., Nathiya, D., et al. (2025) · Brain Research · doi:10.1016/j.brainres.2025.150134 · Cited by 7
Elucidating the Link Between the Modifiable Risk Factors of Alzheimer’s Disease and Neuroinflammation
Schindler, S. M., & Klegeris, A. (2016) · Neurodegenerative Disease Management · doi:10.2217/nmt-2016-0028 · Cited by 5
Glial Contributions to Lafora Disease: A Systematic Review
Vecchia, S. D., Marchese, M., & Santorelli, F. M. (2022) · Biomedicines · doi:10.3390/biomedicines10123103 · Cited by 6
Translocator Protein 18 kDa (TSPO): A Promising Molecular Target for Image-Guided Surgery of Solid Cancers
Wongso, H., Kurniawan, A., Setiadi, Y., Kusumaningrum, C. E., Widyasari, E. M., Wibawa, T. H. A., Mahendra, I. N. B., Febrian, ⁠. B., Sriyani, M. E., Halimah, I., et al. (2023) · Advanced Pharmaceutical Bulletin · doi:10.34172/apb.2024.015 · Cited by 5
“The biological effects could be attributed to the mediation of central benzodiazepine receptors (CBRs) in the CNS. 110 Furthermore, they specifically acted as a positive allosteric modulator on the CNS neurotransmitter, namely gamma amino butyric acid (GABA)-”
Background
The Function and Mechanism of Laminaripentaose Prepared from Curdlan for the Amelioration of the Cognitive Dysfunctions in Obese Mice
Xu, Y., Li, Y., Yan, Q., Mao, X., Yang, S., & Jiang, Z. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c05163 · Cited by 5
Photobiomodulation Therapy at 660 nm Inhibits Hippocampal Neuroinflammation in a Lipopolysaccharide-Challenged Rat Model
Jung, T.-M., Lee, J.-H., Heo, J.-C., & Kim, C. (2024) · Biomedicines · doi:10.3390/biomedicines12112514 · Cited by 5
“Activation of microglia leads to the release of inflammatory cytokines such as nitric oxide (NO), tumor necrosis factor (TNF)- α , and interleukin (IL)-1 β , characteristic markers of AD, PD, MS, and cerebral ischemia [6,10,11].”
Immune responses drive chorioretinitis and retinal pathology after neonatal CMV infection
McCord, J. L., Han, J. Y. S., Staudt, R. E., Philp, N. J., & Snyder, C. M. (2024) · Science Advances · doi:10.1126/sciadv.adn6379 · Cited by 5
3-Dimensional morphological characterization of neuroretinal microglia in Alzheimer’s disease via machine learning
Nassrallah, W. B., Li, H. R., Irani, L., Wijesinghe, P., Hogg, P. W., Hui, L., Oh, J., Mackenzie, I. R., Hirsch‐Reinshagen, V., Hsiung, G. R., et al. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01898-6 · Cited by 9
Advancements in 3D models for studying human iPSC-microglia: Insights into neurodevelopment and neurological disorders
Tiwari, S. K., & Ginhoux, F. (2025) · hLife · doi:10.1016/j.hlife.2025.02.002 · Cited by 5
“…has increasingly elucidated the connections between microglial dysfunction and a spectrum of neuropsychiatric disorders, including schizophrenia, bipolar disorder, and autism, as well as neurodegenerative diseases such as Alzheimer ’ s disease (AD) and Parkinson ’ s disease (PD) [12,17,18].”
Respiratory syncytial virus infection of microglia exacerbates SH-SY5Y neuronal cell injury by inducing the secretion of inflammatory cytokines: A Transwell in vitro study.
Zhang, X., Zhang, X., Yu, H., Wang, Y., Chen, J. C., Wang, Y., Yu, L., Zhu, G.-X., Cao, X., & Huang, S. (2021) · PubMed Central · doi:10.22038/ijbms.2020.49193.11263 · Cited by 5
“Microglial cells can be chronically activated by exposure to a single stimulus (such as lipopolysaccharide) or multiple stimuli for continuous stimulation, leading to the loss of neurons over time (17).”
Background
Microglia Activation in the Midbrain of the Human Neonate: The Effect of Perinatal Hypoxic-Ischemic Injury
Panayotacopoulou, M. T., Papageorgiou, I. E., Pagida, M. A., Katsogridaki, A. E., Chrysanthou‐Piterou, M., Valous, N. A., Halama, N., Patsouris, E., & Konstantinidou, A. E. (2022) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlab135 · Cited by 5
Targeting the pathogenesis and boosting the therapeutic efficacy of Parkinson's disease by advanced nanoparticles
Liu, H., Hua, M., Zheng, Q. Y., Gao, Y., & Li, Z. (2023) · MedComm – Biomaterials and Applications · doi:10.1002/mba2.47 · Cited by 5
Tumors of the Central Nervous System
Suryadevara, R., Fadel, H., Michelhaugh, S. K., Mittal, S., & Parajuli, P. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812218-1.00001-4 · Cited by 6
Protective effect of methanol leaf extract of Cnidoscolus aconitifolius against lipopolysaccharides-induced cortico-hippocampal neuroinflammation, oxidative stress and memory impairment
Babalola, K. T., Oyebanjo, O. T., Adekoya, V. A., Adeniyi, I. A., Ajayi, A. M., & Onasanwo, S. A. (2021) · Oriental Pharmacy and Experimental Medicine · doi:10.1007/s13596-021-00578-3 · Cited by 5
Novel multifunctional nanoliposomes inhibit α-synuclein fibrillization, attenuate microglial activation, and silence the expression of SNCA gene
Jebali, A., Rashidi, M., Keikha, R., Daliri, K., & Outeiro, T. F. (2021) · Neurología · doi:10.1016/j.nrl.2021.08.002 · Cited by 5
Sonidegib Suppresses Production of Inflammatory Mediators and Cell Migration in BV2 Microglial Cells and Mice Treated with Lipopolysaccharide via JNK and NF-κB Inhibition
Nguyen, N. M., Duong, M. T. H., Bui, B. P., Nguyen, P. L., Chen, X., Cho, J., & Ahn, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810590 · Cited by 5
Icaritin inhibits oxidative stress in murine astrocytes by binding to Orai1 to block store‐operated calcium channel
Fan, J., Yu, M., Zhao, Y., Guan, Y., Li, Z., Pan, L., Feng, Q., Yao, J., & Sun, C. (2022) · Chemical Biology & Drug Design · doi:10.1111/cbdd.14193 · Cited by 5
“Moreover, upon inflammation, astrocytes release large amounts of ROS to trigger a series of immune response cascades (Lull & Block, 2007).”
Background
Exposure to metam sodium-based pesticide impaired cognitive performances in adult mice: Involvement of oxidative damage and glial activation
Kaikai, N.-E., Ba-M’hamed, S., Ghanima, A., & Bennis, M. (2023) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2023.116677 · Cited by 5
Oxidative Stress in Neurodegenerative Diseases
Alami, M., Fülöp, T., Boumezough, K., Khalil, A., Zerif, E., & Berrougui, H. (2024) · Springer eBooks · doi:10.1007/978-3-031-69962-7_4 · Cited by 6
Cilostazol attenuates kainic acid-induced hippocampal cell death
Park, Y.-S., Jin, Z. H., Jeong, E. A., Yi, C., Lee, J. Y., Park, I. S., & Roh, G. S. (2017) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2018.22.1.63 · Cited by 5
“KA systemic administration to rodents resulted in increased activation of glial cells, contributing to the progression of neurodegeneration through the production of inflammatory molecules, such as the iron-siderophore binding protein lipocalin-2 (LCN2) [10,11].”
Background
Minocycline protects neurons against glial cells-mediated bilirubin neurotoxicity
Zhou, C., Sun, R., Sun, C., Gu, M., Guo, C., Zhang, J., Du, Y., Gu, H., & Liu, Q. (2019) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2019.11.005 · Cited by 5
“Glial activation is observed in many neurodegenerative disorders (Chen et al., 2010; Lull and Block, 2010) and usually mediated by free radicals (McGeer and McGeer, 1998; von Bernhardi et al.”
Background
A ten year longitudinal examination of the incidence rate and age of childhood encephalopathy diagnoses in an autism spectrum disorder diagnosed cohort
Kern, J. K., Geier, D. A., Homme, K. G., & Geier, M. R. (2020) · Acta Neurobiologiae Experimentalis · doi:10.21307/ane-2020-007 · Cited by 5
Anti-inflammatory Effects of Sanhuang-Siwu-Tang in Lipopolysaccharide-Stimulated RAW264.7 Macrophages and BV2 Microglial Cells
Li, J., Kim, K.-W., Oh, H., & Kim, Y. (2021) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b20-00871 · Cited by 5
Activated Microglia in the Rat Spinal Cord Following Peripheral Axon Injury Promote Glial and Neuronal Plasticity Which is Necessary for Long-Term Neuronal Survival
Goins, J., Henkel, N., Coulibaly, A. P., & Isaacson, L. G. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00853-y · Cited by 6
“In these same images, microglia activation state was assessed by quantifying the number of Iba1+ cells exhibiting 0 or 3–4 primary processes, as activated microglia have shorter and thicker processes or retract their processes completely (Nimmerjahn et al. 2005; Blackbeard et al. 2007; Lull and Block 2010; Kettenmann…”
Method
THSG counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammation
Guo, Z., Zhong, S.-J., Bai, J.-P., Lang, X.-Y., Cao, M., Hu, Y., Qin, X., & Sun, Y. (2025) · Scientific Reports · doi:10.1038/s41598-025-05994-y · Cited by 4
Brain macrophages and pial fibroblasts promote inflammation in a hypomyelination model
Okuno, N., Yamamoto, S., Hamashima, T., Tung, D. S., Okita, N., Fujikawa, M., Kunisawa, T., Takakura, N., Fujimori, T., Mori, H., et al. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02063-3 · Cited by 6
“These data suggest that hypomyelinated cortical lesions were related to neuroinflammatory lesion-like changes, including aberrant vascular formation, glial activation, oxidative neuronal cell damage, and BBB leakage in the cortex of N-PRα-KO mice [33, 43, 47, 70, 100].”
Spinal Cord Injury and Ageing: The Role of Chronic Neuroinflammation
Wang, T., Zhang, Z., Liu, J., Zhang, L., Ni, Q., Sun, B., & Sun, J. (2025) · Aging and Disease · doi:10.14336/ad.2025.10630 · Cited by 4
“Activated glial cells secrete many pro-inflammatory cytokines (such as IL-1β, TNF - α, and IL - 6), significantly amplifying the inflammatory cascade by activating signalling pathways like NF-κB [14].”
Rotenone accelerates endogenous α-synuclein spreading and enhances neurodegeneration in an intra-striatal α-synuclein preformed fibril injected mouse model of Parkinson’s disease
Khan, E., Radwan, N., Ardah, M. T., Kitada, T., & Haque, M. E. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1624593 · Cited by 4
Interplay between CD33 and TREM2 in Alzheimer’s Disease: Potential Mechanistic Insights into Microglial Function in Amyloid Pathology
Akinluyi, E. T., Takahashi, K., Connolly, M. G., Poon, W. W., & Macauley, M. S. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00805 · Cited by 5
The Spectrum of Microglia: Decoding Heterogeneity and Plasticity for Therapeutic Gain in Neurological Disorders
Gao, C., Lin, Z., Chen, Y., Gan, R., Wang, K., He, X., & Han, H. (2025) · Neuropharmacology and Therapy · doi:10.15212/npt-2025-0015 · Cited by 5
“This shift can induce a detrimental, self-perpetuating primed state causing microglia to transition from a neuroprotective to a neurotoxic functional profile [6,7].”
Persistent microglial activation following neonatal CMV infection mediates neurodegeneration
McCord, J. L., Chatterjee, D., Han, J. Y. S., Scoles, D., Smeyne, R. J., Philp, N. J., & Snyder, C. M. (2026) · Science Advances · doi:10.1126/sciadv.adz1686 · Cited by 4
“Inflammatory and DAM have been linked to the development of pathology in neurodegenerative diseases ( 42, 52, 54, 57, 76 ).”
The role of blood-brain barrier integrity in the pathophysiology and progression of psychiatric disorders
Konstantinou, G., & Warsh, J. J. (2026) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2026.106658 · Cited by 6
Induction of Neural Differentiation and Protection by a Novel Slow-Release Nanoparticle Estrogen Construct in a Rat Model of Spinal Cord Injury
Haque, A., Zaman, V., Drasites, K. P., Matzelle, D. D., Sawant, S., Vertegel, A. A., Varma, A. K., & Banik, N. L. (2024) · Neurochemical Research · doi:10.1007/s11064-024-04289-4 · Cited by 5
Characterization of Walnut Oil and Evaluation of Its Neuroprotective Effects in an In Vitro Model of Parkinson’s Disease
Filaferro, M., Avallone, R., Rustichelli, C., & Vitale, G. (2024) · Molecules · doi:10.3390/molecules29235718 · Cited by 4
“Although specific microglial products were not identified in this study, others have suggested that neurotoxic factors, such as superoxide, myeloperoxidase, prostaglandins, NO, glutamate, IL-1b, and TNFa, may play a role in causing toxicity to neuron-like cells under in vitro models [39,40].”
α-Phellandrene: A Promising Natural Remedy for Rotenone-Induced Parkinson's Disease
Kumar, R., Arora, S., Alam, S., Rashid, M., & Kumar, S. (2025) · Recent Advances in Food Nutrition & Agriculture · doi:10.2174/012772574x341801241218051720 · Cited by 4
Neuromodulation influences T lymphocyte calcium signaling and alpha synuclein clearance: implications for Parkinson’s disease
Ross, A., Prowse, N. A., Zhang, H., Hayley, S. P., & Hongyu, S. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1627305 · Cited by 4
“Regardless of the disease origins, reactive microglia are present in virtually all PD brains and inﬁltrating peripheral immune cells often accompany this neuroinﬂammatory feature (Lull and Block, 2010; Sanchez-Guajardo et al., 2010).”
Influential
Identification of perioperative neurocognitive dysfunction biomarkers in cerebrospinal fluid with quantitative proteomic approach in patients undergoing transurethral resection of prostate with combined spinal and epidural analgesia
Luo, T.-Y., Zhou, W., Xiang, G.-F., Zhang, Y., & Liu, Q. (2022) · Medicine · doi:10.1097/md.0000000000030448 · Cited by 3
Pro-Inflammatory and Pro-Apoptotic Effects of the Non-Protein Amino Acid L-Azetidine-2-Carboxylic Acid in BV2 Microglial Cells
Piper, J. A., Jansen, M. I., Broome, S. T., Rodgers, K. J., Musumeci, G., & Castorina, A. (2022) · Current Issues in Molecular Biology · doi:10.3390/cimb44100308 · Cited by 4
“Current evidence suggests that prolonged microglial polarisation may promote neuronal damage and aggravate oligodendroglial pathology, similar to what we see in neuroinflammatory diseases such as MS [17,18].”
Background
NADPH oxidase 4 inhibition is a complementary therapeutic strategy for spinal muscular atrophy
Khoury, M. E., Biondi, O., Bruneteau, G., Sapaly, D., Bendris, S., Bézier, C., Clerc, Z., Akar, E. A., Weill, L., Eid, A. A., et al. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1242828 · Cited by 4
“, 2020), thought to participate in neuron degeneration (Lull and Block, 2010; Hickman et al., 2018), we investigated whether NOX4 inhibition by GKT137831 could limit also the activation of the microglia in the spinal cord of severe type SMA-like mice.”
Background
Glial cells of the central and peripheral nervous systems: An overview of existing research
Haywood, R. E. (2024) · Journal of Applied Neurosciences · doi:10.4102/jan.v3i1.13 · Cited by 4
“Microglia mediate phagocytosis of cellular debris resulting from apoptosis and normal cell death and neural injury (Lull & Block, 2010).”
Background
Reporting the anti-neuroinflammatory potential of selected spondias mombin flavonoids through network pharmacology and molecular dynamics simulations
Afees, O. J., Arietarhire, L. O., Soremekun, O. E., Olugbogi, E. A., Aribisala, P. O., Alege, P. E., Adeleke, S. O., Afolabi, T. O., & Sodipo, A. O. (2024) · In Silico Pharmacology · doi:10.1007/s40203-024-00243-y · Cited by 6
“Inflammation in tissue pathology indicates the long-term effects of inflammatory stimuli or a malfunction in the regular repair mechanisms, which may then result in the production of neurotoxic substances that worsen disease states (Lull et al. 2010; Sarma 2014).”
Postencephalitic Parkinsonism: Unique Pathological and Clinical Features—Preliminary Data
Strobel, S., Sian‐Hülsmann, J., Tappe, D., Jellinger, K. A., Riederer, P. F., & Monoranu, C. (2024) · Cells · doi:10.3390/cells13181511 · Cited by 5
“Additionally, microgliosis may induce an imbalance leading to a greater secretion of pro-inflammatory (such as tumor necrosis factor-α , interleukin-1 β ) than anti-inflammatory factors, resulting in chronic neuroinflammation [78].”
Background

Authors: Lull, M. E., & Block, M. L.
Affiliations: Virginia Commonwealth University (US)
Corresponding author: Block, Michelle L.
ORCID: Lull, Melinda E.
Block, Michelle L.
Venue: Neurotherapeutics
Publisher: Elsevier BV
Published: 2010-10
Volume: 7
Issue: 4
Pages: 354-365
ISSN: 1878-7479 (ISSN-L)
DOI: 10.1016/j.nurt.2010.05.014
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 4696 d)
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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Microglial Activation and Chronic Neurodegeneration

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