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Neuroinflammation and α-Synuclein Dysfunction Potentiate Each Other, Driving Chronic Progression of Neurodegeneration in a Mouse Model of Parkinson’s Disease
Open accessAbstract
Background: Mechanisms whereby gene–environment interactions mediate chronic, progressive neurodegenerative processes in Parkinson’s disease (PD)—the second most common neurodegenerative disease—remain elusive. Objective: We created a two-hit [neuroinflammation and mutant α-synuclein (α-syn) overexpression] animal model to investigate mechanisms through which mutant α-syn and inflammation work in concert to mediate chronic PD neurodegeneration. Methods: We used an intraperitoneal injection of the inflammogen lipopolysaccharide (LPS; 3 × 106 EU/kg) to initiate systemic and brain inflammation in wild-type (WT) mice and transgenic (Tg) mice overexpressing human A53T mutant α-syn. We then evaluated nigral dopaminergic neurodegeneration, α-syn pathology, and neuroinflammation. Results: After LPS injection, both WT and Tg mice initially displayed indistinguishable acute neuroinflammation; however, only Tg mice developed persistent neuroinflammation, chronic progressive degeneration of the nigrostriatal dopamine pathway, accumulation of aggregated, nitrated α-syn, and formation of Lewy body-like inclusions in nigral neurons. Further mechanistic studies indicated that 4-week infusion of two inhibitors of inducible nitric oxide synthase and NADPH oxidase, major free radical–generating enzymes in activated microglia, blocked nigral α-syn pathology and neurodegeneration in LPS-injected Tg mice. Conclusions: Microglia-derived oxidative stress bridged neuroinflammation and α-syn pathogenic alteration in mediating chronic PD progression. Our two-hit animal model involving both a genetic lesion and an environmental trigger reproduced key features of PD and demonstrated synergistic effects of genetic predisposition and environmental exposures in the development of PD. The chronic progressive nature of dopaminergic neurodegeneration, which is absent in most existing PD models, makes this new model invaluable for the study of mechanisms of PD progression.
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“Not only has chronic neuroinflammation been shown to increase α-synuclein deposition in various synucleinopathy animal models (51–56), but when these animals were treated with drugs to reduce neuroinflammation, α-synuclein neuropathology also decreased (57, 58).”
From LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies (2020) · cites this paper as [53]
In the citing paper
“This supports a dual-hit hypothesis for PD: elevated endotoxin plus aggregable α-synuclein results in neurodegeneration.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [101]
In the citing paper
“A single injection of peripheral endotoxin into wild-type mice and transgenic mice (expressing human A53T mutant α-synuclein) resulted in indistinguishable acute neuroinflammation, but only the transgenic mice treated with endotoxin developed persistent neuroinflammation, aggregated α-synuclein, progressive degeneration of dopamine neurons and Lewy body-like inclusions in nigral neurons [101].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [101]
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“To obtain adequate sample sizes of each stage, cases were from several different LB disease classifications, including incidental Lewy body disease (ILBD), Alzheimer’s disease with Lewy bodies (ADLB), PD, PD with dementia (PDD) and DLB.”
BackgroundInfluentialSerapide, M. F., L’Episcopo, F., Tirolo, C., Testa, N., Caniglia, S., Giachino, C., & Marchetti, B. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00024 · Cited by 32
Integration of iPSC-Derived Microglia into Brain Organoids for Neurological Research
Mrza, M. A., He, J., & Wang, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063148 · Cited by 31
Almohmadi, N. H., Al-Kuraishy, H. M., Al-Gareeb, A. I., Albuhadily, A. K., Abdelaziz, A. M., Jabir, M. S., Alexiou, A. T., Papadakis, M., & Batiha, G. E. (2025) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2025.111349 · Cited by 35
“Dextromethorphan inhibits neuroinflammation in PD models by attenuating α -Syn-induced microglial activation and release of pro-inflammatory cytokines (Gao et al., 2011).”
Characterization of a Parkinson’s disease rat model using an upgraded paraquat exposure paradigm
Cristóvão, A. C., Campos, F. L., Je, G., Esteves, M., Guhathakurta, S., Yang, L., Beal, M. F., Fonseca, B. M., Salgado, A. J., Queiroz, J. A., et al. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14683 · Cited by 33
Samidurai, M., Tarale, P., Janarthanam, C., Gomez-Estrada, C., Gordon, R., Zenitsky, G. D., Jin, H., Anantharam, V., Kanthasamy, A. G., & Kanthasamy, A. (2020) · Cells · doi:10.3390/cells9081831 · Cited by 31
More, S. V., Kumar, H., Kim, I., Koppula, S., Kim, B.-W., & Choi, D. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/18715273113129990059 · Cited by 31
van Vuuren, M. J., Nell, T. A., Carr, J. A., Kell, D. B., & Pretorius, E. (2020) · Biomolecules · doi:10.3390/biom11010030 · Cited by 33
Oxidative Stress, Neuroinflammation, and Neurodegeneration
Gao, H., Zhou, H., & Hong, J. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1071-7_5 · Cited by 30
Self-citationZheng, W., Zheng, X.-X., Liu, S., Ouyang, H., Levitt, R., Candiotti, K., & Hao, S.-L. (2012) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2012.03.068 · Cited by 30
Trudler, D., Nash, Y., & Frenkel, D. (2015) · Journal of Neural Transmission · doi:10.1007/s00702-015-1399-z · Cited by 31
“…were also linked to PD. High mobility group box 1 (HMGB1), a type of damage-associated molecular pattern molecule (DAMP), is increased following exposure of microglia to several PD-inducing toxins, such as rotenone and toxin 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), (Gao et al. 2011b).”
BackgroundFifel, K., Piggins, H., & Deboer, T. (2016) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2015.02.005 · Cited by 30
Luna-Herrera, C., Martínez-Dávila, I. A., Soto-Rojas, L. O., Flores-Martinez, Y. M., Fernandez-Parrilla, M. A., Ayala-Dávila, J., León‐Chávez, B. A., Soto-Rodríguez, G., Blanco-Álvarez, V. M., López-Salas, F. E., et al. (2020) · Journal of Immunology Research · doi:10.1155/2020/5907591 · Cited by 30
“These antecedents and the finding that pathological α-synuclein aggregates can induce neuroinflammation [84, 85] strongly suggest that the acute BSSG intranigral administration also leads to neuroinflammation in the whole brain.”
Stoll, A. C., & Sortwell, C. E. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105804 · Cited by 29
“Many studies have investigated the neuroinflammatory consequences of nigral degeneration and/or α-syn aggregation using neurotoxicant models (Cicchetti et al., 2002; Forno et al., 1993; Koprich et al., 2008; Kurkowska-Jastrze et al., 1999; Miklossy et al., 2006); transgenic overexpression models of human wild type or…”
BackgroundInfluentialKan, M., Yang, T., Fu, H. Q., Fan, L., Wu, Y., Terrando, N., & Wang, T. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00175 · Cited by 29
“Effects of PDTC on Astrocytes and IL-1β Expression in the Hippocampus Previous studies have shown that acute systemic inflammation triggered by a single administration of LPS resulted in chronic neuroinflammation (Qin et al., 2007; Gao et al., 2011).”
BackgroundResultIntracellular Alpha-Synuclein and Immune Cell Function
Grozdanov, V., & Danzer, K. M. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.562692 · Cited by 27
“Many studies have addressed neuroinflammation in animal models of synucleinopathies, and some of them have utilized systemic, not neuron-limited approaches (Cicchetti et al., 2002; Qin et al., 2007; Gao et al., 2011).”
BackgroundKarim, S., Mirza, Z., Chaudhary, A., Abuzenadah, A. M., Gari, M. A., & Al-Qahtani, M. H. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17020250 · Cited by 29
“5) was one of the differentially expressed gene identified in the microarray meta-analysis, which was validated [5] and reported to be associated with neuroinflammation [26].”
BackgroundHerpesvirus Infections and Risk of Parkinson’s Disease
Camacho‐Soto, A., Faust, I. M., Racette, B. A., Clifford, D. B., Checkoway, H., & Nielsen, S. S. (2020) · Neurodegenerative Diseases · doi:10.1159/000512874 · Cited by 27
Parkinson’s Disease: A Nanotheranostic Approach Targeting Alpha-Synuclein Aggregation
Zoey, F. L., Palanivel, M., Padmanabhan, P., & Gulyás, B. Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.707441 · Cited by 27
N-Acetyl cysteine prevents synergistic, severe toxicity from two hits of oxidative stress
Unnithan, A. S., Jiang, Y., Rumble, J. L., Pulugulla, S. H., Posimo, J. M., Gleixner, A. M., & Leak, R. K. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.12.023 · Cited by 27
Olesen, M. N., Christiansen, J. R., Petersen, S. V., Jensen, P. H., Pasławski, W., Romero‐Ramos, M., & Sánchez-Guajardo, V. (2018) · Heliyon · doi:10.1016/j.heliyon.2018.e00513 · Cited by 28
“…of animals inoculated with LPS (10,000 EU/g) to establish the specificity of the α-syn-induced changes as compared to the well-established pro-inflammatory response to LPS, which is known to induce immune activation not only in periphery but also in brain (Castano et al., 2002; Gao et al., 2011).”
BackgroundMotyl, J. A., Strosznajder, J. B., Wencel, A., & Strosznajder, R. P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126277 · Cited by 28
Rauschenberger, L., Behnke, J. K., Grotemeyer, A., Knörr, S., Volkmann, J., & Ip, C. W. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105798 · Cited by 29
Shahaduzzaman, M., Acosta, S., Bickford, P. C., & Borlongan, C. V. (2013) · Medical Hypotheses · doi:10.1016/j.mehy.2013.07.025 · Cited by 26
“neuroinflammation has been reported an in two-hit mouse model of PD [16].”
BackgroundProgressive Supranuclear Palsy Syndrome: An Overview
Ichikawa-Escamilla, E., Velasco-Martínez, R. A., & Adalid-Peralta, L. V. (2024) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2024.04.008 · Cited by 31
“As in AD with tau, neuroinflammation is closely related to α -synuclein in PD. Specifically, the bridge between neuroinflammation and neuro-degeneration in PD is thought to be microglial-derived oxidative stress (Gao et al., 2011).”
BackgroundAdebayo, O. G., Asiwe, J. N., Ben‐Azu, B., Aduema, W., Onyeleonu, I., Akpotu, A. E., Wopara, I., Kolawole, T. A., Umoren, E. B., Igbokwe, V. U., et al. (2022) · Journal of Food Biochemistry · doi:10.1111/jfbc.14253 · Cited by 25
Gupta, S. P., Yadav, S., Singhal, N. K., Tiwari, M. N., Mishra, S. K., & Singh, M. P. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8517-4 · Cited by 26
Zhang, Y., Bolivar, V. J., & Lawrence, D. A. (2013) · Toxicological Sciences · doi:10.1093/toxsci/kft023 · Cited by 25
“Brain inflammation has been suggested to be involved in many neurodevelopmental diseases (Gao et al., 2011; Lee et al., 2010; Mondal et al., 2008).”
BackgroundSong, S., Liu, J., Zhang, F., & Hong, J. (2020) · Scientific Reports · doi:10.1038/s41598-020-72202-4 · Cited by 25
Self-citationHeinemann, S. D., Posimo, J. M., Mason, D. M., Hutchison, D. F., & Leak, R. K. (2016) · Hippocampus · doi:10.1002/hipo.22580 · Cited by 24
“The two-hit hypothesis of neurodegeneration has been proposed as a model for both Alzheimer’s and Parkinson’s disease (Cory-Slechta et al., 2005; Hawkes et al., 2007; Zhu et al., 2007; Boger et al., 2010; Gao et al., 2011).”
BackgroundResultVertebrate food products as a potential source of prion-like α-synuclein
Killinger, B. A., & Labrie, V. (2017) · npj Parkinson s Disease · doi:10.1038/s41531-017-0035-z · Cited by 23
Revisiting Alpha-Synuclein Pathways to Inflammation
Lyra, P., Machado, V., Rota, S., Chaudhuri, К. R., Botelho, J., & Mendes, J. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087137 · Cited by 24
“The transport of toxic α-Syn species through the microbiota–gut–brain axis ultimately results in the loss of dopaminergic neurons and causes a microglial inflammatory response that is in the pathogenesis of α-synucleinopathies [83].”
BackgroundHuang, C., Lin, F., Wang, G., Lu, D., Wu, Q., Liu, J., Shi, J., & Zhang, F. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/7927568 · Cited by 23
“In addition, NO could react with ROS to form highly toxic intermediates such as peroxynitrite to induce DA neuronal damage [22].”
BackgroundSelf-citationSchildt, A., Walker, M. D., Dinelle, K., Miao, Q., Schulzer, M., OʼKusky, J. R., Farrer, M. J., Doudet, D. J., & Sossi, V. (2018) · Journal of Parkinson s Disease · doi:10.3233/jpd-181446 · Cited by 25
“For example, a comparably designed study using -synuclein A53T transgenic mice subjected to one peripheral LPS injection at the age of 7 months showed persistent inflammation in the SN and striatum and progressive neurodegeneration of the DA system compared to NT and saline treated TG mice [17].”
Roca, F., Lang, P. O., & Chassagne, P. (2019) · Handbook of clinical neurology · doi:10.1016/b978-0-12-804766-8.00007-8 · Cited by 23
Neuroprotective approaches to halt Parkinson's disease progression
Sola, P., Krishnamurthy, P. T., Kumari, M., Byran, G., Gangadharappa, H. V., & Garikapati, K. K. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105380 · Cited by 21
Dong, J., Liu, X., Wang, Y. Y., Cai, H., & Le, W. (2020) · Glia · doi:10.1002/glia.23826 · Cited by 22
“In addition, systemic administration of LPS by intraperitoneal injection leads to a progressive and selective degeneration of DAergic neurons in several mouse models (Frank-Cannon et al., 2008; Gao et al., 2011; Qin et al., 2007).”
BackgroundInfluentialBrezzo, G., Simpson, J. E., Ameen‐Ali, K. E., Berwick, J., & Martin, C. J. (2020) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2020.100074 · Cited by 26
“Mounting evidence highlights inflammation as a major factor in the development of many neurodegenerative diseases (Cunningham, 2013; Frank-Cannon et al., 2009; Gao et al., 2011; Heppner et al., 2015).”
BackgroundCarelli, S., Giallongo, T., Gombalová, Z. T., Rey, F., Gorio, M. C., Mazza, M., & Giulio, A. M. D. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1375-2 · Cited by 22
Metadata
- Authors
- Gao, H.-M., Zhang, F., Zhou, H., Kam, W., Wilson, B., & Hong, J.-S.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Gao, Hui-Ming
- Venue
- Environmental Health Perspectives
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-01-18
- Volume
- 119
- Issue
- 6
- Pages
- 807-814
- ISSN
- 0091-6765 (ISSN-L)
- 1552-9924
- PMC
- PMC3114815
- OpenAlex
- W1971599063
- Cited by
- 355
- References
- 46
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 36 · 2023: 23 · 2022: 28 · 2021: 37 · 2020: 39 · 2019: 17 · 2018: 28 · 2017: 20 · 2016: 18 · 2015: 16 · 2014: 19 · 2013: 18 · 2012: 19
- FWCI
- 13.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/licenses/by/4.0/ (vor, 2537 d)
- Locations
- Environmental Health Perspectives (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, neuroinflammation, alpha-synuclein, lipopolysaccharide, two-hit model, gene-environment interaction, microglia, oxidative stress, inducible nitric oxide synthase, NADPH oxidase, dopaminergic neuron loss, nigrostriatal pathway, Lewy bodies, chronic neurodegeneration
- MeSH terms
- Amidines, Animals, Benzylamines, Disease Models, Animal, Injections, Intraperitoneal, Lipopolysaccharides, Nerve Degeneration, Onium Compounds, Parkinson Disease, Substantia Nigra, Lewy Bodies, Oxidative Stress, NADPH Oxidases, Neurodegenerative Diseases, Animals, Genetically Modified, Mice, alpha-Synuclein, Nitric Oxide Synthase Type II
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