Cited by 355Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsNuclear Receptors and Signaling

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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

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Gao, Hui-Ming, Zhang, Feng, Zhou, Hui, Kam, Wayneho, Wilson, Belinda, Hong, Jau-Shyong·2011·Environmental Health Perspectives

DOI 10.1289/ehp.1003013PMC PMC3114815

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Abstract

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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Figure 1 α-Syn Tg mice were more sensitive to inflammation-mediated neurotoxicity. (A) Time-dependent loss of nigral DA neurons in α-syn Tg mice, but not WT mice, after LPS injection. (B) Densitometry analysis revealed a 46% decrease in striatal TH immunostaining in Tg mice 5 months after LPS injection. In A and B, numbers within the bars indicate the number of mice in each group at each time point. (C and D) Representative brain images with TH immunostaining 5 months after LPS injection indicate prominent dopaminergic lesions of SN (C) and striatum (D) in Tg mice but not in WT mice. (E) In the SN of LPS-injected Tg mice, the loss of DA neurons (double-labeled with anti-TH antibody in cytoplasm and anti–Neu-N antibody in nuclei) 5 months after LPS was greater than that of non-DA neurons (green nuclear Neu-N staining only). The inset shows a double-labeled DA neuron. In inset, bar = 10 μm. *p < 0.05 compared with the corresponding NS-injected control.CC0 · PubMed Central

Figure 2 Accumulation of insoluble and aggregated α-syn after LPS injection. (A) Five months after treatment, LPS-injected Tg mice accumulated more α-syn in the whole brain than did NS-injected Tg mice, as shown by immunoblotting using SYN211 antibody (specific for human α-syn) and summarized in the graph. (B) Sequential extraction detected RIPA-insoluble α-syn in midbrains of LPS-injected Tg mice; α-syn of WT mice was recovered only in HS- and HST-soluble fractions. In A and B, each lane is the most representative sample from among at least three different animals. (C). In contrast with diffuse and faint α-syn staining observed in the SN of NS-injected Tg mice 5 months after the injection (left), α-syn (red) in LPS-injected Tg mice (center) appeared mainly in perinuclear locations and formed aggregates; magnifications (right) are from areas indicated in the LPS section (center). *p < 0.05 compared with the NS-injected control.CC0 · PubMed Central

Figure 3 Nitration of aggregated α-syn and formation of cytoplasmic inclusions in Tg mice 5 months after LPS injection. (A) Nitrated human α-syn (labeled with nSYN514 antibody) formed aggregates and was mainly perinuclear in the SN of LPS-injected Tg mice (center), whereas nSYN514 staining in NS-injected Tg mice (left) was scant. Magnifications (right) are from areas shown in the LPS section. (B) The SN of LPS-injected Tg mice contained human α-syn aggregates (red) in TH-IR neurons (green). (C) Cytoplasmic inclusions containing nitrated human α-syn (brown) in nigral neurons (with nuclei stained in dark blue) indicated by red arrows in LPS-injected Tg mice (center) and magnified photomicrographs (right) from the LPS section. The SN of NS-injected Tg mice (left) did not exhibit obvious staining for nitrated α-syn. (D) Western blotting shows nitrated human α-syn in midbrain extracts from LPS-injected Tg mice but not NS-injected Tg mice. (E) The accumulation of nitrated human α-syn was observed primarily in RIPA and SDS fractions from midbrains of Tg mice. At least four mice in each group were used for immunostaining and immunoblotting. For magnifications in C, bars = 10 μm.CC0 · PubMed Central

Figure 4 Association between progressive nigral neurodegeneration and prolonged neuroinflammation. Double-label immunofluorescence shows loss of TH-positive DA neurons and degeneration of DA fibers in the SN of α-syn Tg mice 5 months after LPS injection. Only in LPS-injected Tg mice did microglia show active morphology: elevated expression of Iba-1 (red), larger size, irregular shape, and increased numbers in the SN. Microglia of WT mice exhibit resting ramified morphology. Magnifications (right) are from areas indicated in the merged column. All images are representative samples from among at least three different animals in each group.CC0 · PubMed Central

Figure 5 Association of neurodegeneration with chronic α-syn accumulation and prolonged neuroinflammation. Five months after LPS injection, Tg mice displayed significant decreases in TH levels, marked up-regulation of multiple inflammatory markers (Mac1, Iba-1, gp91, iNOS, and COX-2), and accumulation of α-syn in the SN (A and B) and striatum (C and D). NS-injected 12-month-old Tg mice did not show overt changes in levels of TH, α-syn, or inflammatory markers, in contrast with 2-month-old Tg mice. Graphs (B and D) show the ratio of densitometry values (mean ± SE) of each examined protein, and β-actin was normalized to each respective NS-injected control. All immunoblot lanes are representative samples from among at least three different animals in each group. *p < 0.05 compared with corresponding NS-injected control mice.CC0 · PubMed Central

Figure 6 Inhibition of iNOS and NADPH oxidase prevent chronic dopaminergic neurodegeneration and α-syn pathology in LPS-injected Tg mice. (A) Immunoblotting analysis of midbrain proteins extracted by 2% SDS buffer indicates that a 4-week infusion of 1400W and DPI blunted up-regulation of inflammatory markers (Mac1, iNOS, and gp91phox), attenuated loss of TH, and reduced accumulation of nitrated α-syn in Tg mice 3 months after LPS injection. (B) Densitometry analysis of proteins and β-actin examined in A; Results are mean ± SE normalized to the corresponding NS-injected control. (C) Accumulation of nitrated human α-syn with low solubility in RIPA and SDS fractions from midbrains of Tg mice 3 months after LPS injection, which was blocked by 1400W and DPI. (D) Blockage of chronic degeneration of nigral DA neurons in α-syn Tg mice 3 months after LPS injection by 1400W and DPI. (E) Representative brain images of α-syn Tg mice 3 months after LPS indicate that a 4-week infusion of 1400W and DPI dampened chronic microglial activation, attenuated accumulation of α-syn, and reduced nigral DA lesions. Insets are magnified photomicrographs of corresponding images. In insets, bar = 25 μm. For immunoblotting and immunostaining, n = 4 mice per group. *p < 0.05 compared with corresponding NS-injected control mice; #p < 0.05 compared with corresponding LPS-injected mice.CC0 · PubMed Central

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Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382 · cited 1×
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Background
Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
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BackgroundSelf-citation
AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
Krüger, R., Kuhn, W., Müller, T., Woitalla, D., Graeber, M., Kösel, S., Przuntek, H., Epplen, J. T., Schols, L., & Riess, O. (1998) · Nature Genetics · doi:10.1038/ng0298-106 · Cited by 3,836 · cited 1×
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Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains
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BackgroundSelf-citation
α-synuclein locus duplication as a cause of familial Parkinson's disease
Chartier-Harlin, M.-C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S., Levecque, C., Larvor, L., Andrieux, J., Hulihan, M., et al. (2004) · The Lancet · doi:10.1016/s0140-6736(04)17103-1 · Cited by 2,029 · cited 1×
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Neuroinflammation in Parkinson’s disease: A target for neuroprotection?
Hirsch, E. C., & Hunot, S. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70062-6 · Cited by 1,984 · cited 1×
“Emerging evidence has indicated that neuroinflammation contributes to PD (Block et al. 2007; Gao and Hong 2008; Hirsch and Hunot 2009).”
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“Intriguingly, an inflammatory environment is known to enhance aSyn aggregation, which may further activate microglia upon contact and promote a feed-forward cascade that leads to additional aSyn aggregation and propagation and progression of disease (Gao et al., 2011).”
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Research Neuroinflammation and α-Synuclein Dysfunction Potentiate Each Other, Driving Chronic Progression of Neurodegeneration in a Mouse Model of Parkinson’s Disease
Gao, H.-M., Zhang, F., Zhou, H., Kam, W., Wilson, B. C., & Hong, J.-S. (2013)
Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson’s disease overexpressing human alpha synuclein
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Neuroinflammation and Oxidation/Nitration of α-Synuclein Linked to Dopaminergic Neurodegeneration
Gao, H., Kotzbauer, P. T., Uryu, K., Leight, S., Trojanowski, J. Q., & Lee, V. M. ‐. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0143-07.2008 · Cited by 453
Peripheral inflammation influences α‐synuclein toxicity and neuropathology in Parkinson’s disease models
Vitola, P. L., Balducci, C., Baroni, M., Santamaria, G., Artioli, L., Castiglioni, M., Caldinelli, L., Pollegioni, L., & Forloni, G. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.043358 · Cited by 2
Temporal Evolution of Inflammation and Neurodegeneration With Alpha-Synuclein Propagation in Parkinson's Disease Mouse Model
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Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
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Neurodegeneration and neuroinflammation are linked, but independent of alpha‐synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease
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Alpha-synuclein and neuroinflammation in Parkinson's disease
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Neurodegeneration and neuroinflammation are linked, but independent of α -synuclein inclusions, in a seeding/spreading mouse model of Parkinson’s diseasePreprint
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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
ORCID: Gao, Hui-Ming
Zhang, Feng
Zhou, Hui
Kam, Wayneho
Hong, Jau-Shyong
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
DOI: 10.1289/ehp.1003013
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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Neuroinflammation and α-Synuclein Dysfunction Potentiate Each Other, Driving Chronic Progression of Neurodegeneration in a Mouse Model of Parkinson’s Disease

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