Alpha-synuclein pathology enhances peripheral and CNS immune responses to bacterial endotoxins
Increasing evidence points to infectious diseases as contributor to the pathogenesis of neurodegeneration in Parkinson's disease (PD), probably driven by a peripheral and CNS inflammatory response together with alpha-synuclein (aSyn) pathology. Pro-inflammatory lipopolysaccharide (LPS) endotoxi...
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003759 |
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| author | Anna-Sophia Hartke Cara S. Schreiber Kristina Lau Ivo Wiesweg Inken Waltl Ulrich Kalinke Franziska Richter Christopher Käufer |
| author_facet | Anna-Sophia Hartke Cara S. Schreiber Kristina Lau Ivo Wiesweg Inken Waltl Ulrich Kalinke Franziska Richter Christopher Käufer |
| author_sort | Anna-Sophia Hartke |
| collection | DOAJ |
| description | Increasing evidence points to infectious diseases as contributor to the pathogenesis of neurodegeneration in Parkinson's disease (PD), probably driven by a peripheral and CNS inflammatory response together with alpha-synuclein (aSyn) pathology. Pro-inflammatory lipopolysaccharide (LPS) endotoxin is suggested as a risk factor, and LPS shedding gram-negative bacteria are more prevalent in the gut-microbiome of PD patients. Here, we investigated whether LPS could contribute to the neurodegenerative disease progression via neuroinflammation, especially under conditions of aSyn pathology. To investigate this, we created a double-hit model based on the Thy1-aSyn mouse line (line 61), an established aSyn-overexpression model of PD, exposed to a single intraperitoneal injection of LPS at a dose of 0.8 mg/kg (equivalent to approximately 1,200,000 EU/kg). Clinical parameters, flow cytometry of blood and immune cells in the brain, brain immunohistology and motor behavior were evaluated over time. As expected, the LPS dosage induced transient acute symptoms and mild weight loss in mice, with full recovery after 7 days. In aSyn over-expressing mice, this single low dose of LPS was sufficient to alter the expression of specific markers on blood and brain immune cells and induced brain region-specific microgliosis that were present at 7 days post LPS injection. At 14 days post injection of LPS, aSyn expression was reduced in wild-type mice, indicating a specific response of the endogenous protein to the endotoxin. At this early time point, motor behavior is not yet robustly impacted by the observed pathological alterations. In conclusion, aSyn pathology renders the peripheral and central immune response more sensitive to a single low dose of bacterial endotoxin, which mimics a transient dysbiosis or gut infection. Thus, this data suggests that such peripheral triggers should be monitored in PD patients for instance by blood immune cell response as biomarkers. Furthermore, results from this study lend further support to the development of treatments aiming to reduce the impact of bacterial dysbiosis as a promising strategy to mitigate PD progression. |
| format | Article |
| id | doaj-art-a276e6b46ba748cdaeba50929f822b8d |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-a276e6b46ba748cdaeba50929f822b8d2025-01-24T04:44:37ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106773Alpha-synuclein pathology enhances peripheral and CNS immune responses to bacterial endotoxinsAnna-Sophia Hartke0Cara S. Schreiber1Kristina Lau2Ivo Wiesweg3Inken Waltl4Ulrich Kalinke5Franziska Richter6Christopher Käufer7Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience (ZSN), Hannover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience (ZSN), Hannover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience (ZSN), Hannover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, GermanyInstitute for Experimental Infection Research, TWINCORE, Center for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625 Hannover, GermanyInstitute for Experimental Infection Research, TWINCORE, Center for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625 Hannover, Germany; Center for Systems Neuroscience (ZSN), Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience (ZSN), Hannover, Germany; Corresponding authors at: Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany.Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany; Corresponding authors at: Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany.Increasing evidence points to infectious diseases as contributor to the pathogenesis of neurodegeneration in Parkinson's disease (PD), probably driven by a peripheral and CNS inflammatory response together with alpha-synuclein (aSyn) pathology. Pro-inflammatory lipopolysaccharide (LPS) endotoxin is suggested as a risk factor, and LPS shedding gram-negative bacteria are more prevalent in the gut-microbiome of PD patients. Here, we investigated whether LPS could contribute to the neurodegenerative disease progression via neuroinflammation, especially under conditions of aSyn pathology. To investigate this, we created a double-hit model based on the Thy1-aSyn mouse line (line 61), an established aSyn-overexpression model of PD, exposed to a single intraperitoneal injection of LPS at a dose of 0.8 mg/kg (equivalent to approximately 1,200,000 EU/kg). Clinical parameters, flow cytometry of blood and immune cells in the brain, brain immunohistology and motor behavior were evaluated over time. As expected, the LPS dosage induced transient acute symptoms and mild weight loss in mice, with full recovery after 7 days. In aSyn over-expressing mice, this single low dose of LPS was sufficient to alter the expression of specific markers on blood and brain immune cells and induced brain region-specific microgliosis that were present at 7 days post LPS injection. At 14 days post injection of LPS, aSyn expression was reduced in wild-type mice, indicating a specific response of the endogenous protein to the endotoxin. At this early time point, motor behavior is not yet robustly impacted by the observed pathological alterations. In conclusion, aSyn pathology renders the peripheral and central immune response more sensitive to a single low dose of bacterial endotoxin, which mimics a transient dysbiosis or gut infection. Thus, this data suggests that such peripheral triggers should be monitored in PD patients for instance by blood immune cell response as biomarkers. Furthermore, results from this study lend further support to the development of treatments aiming to reduce the impact of bacterial dysbiosis as a promising strategy to mitigate PD progression.http://www.sciencedirect.com/science/article/pii/S0969996124003759Alpha-SynucleinParkinson's diseaseLipopolysaccharideNeurodegenerative diseaseNeuroinflammation |
| spellingShingle | Anna-Sophia Hartke Cara S. Schreiber Kristina Lau Ivo Wiesweg Inken Waltl Ulrich Kalinke Franziska Richter Christopher Käufer Alpha-synuclein pathology enhances peripheral and CNS immune responses to bacterial endotoxins Neurobiology of Disease Alpha-Synuclein Parkinson's disease Lipopolysaccharide Neurodegenerative disease Neuroinflammation |
| title | Alpha-synuclein pathology enhances peripheral and CNS immune responses to bacterial endotoxins |
| title_full | Alpha-synuclein pathology enhances peripheral and CNS immune responses to bacterial endotoxins |
| title_fullStr | Alpha-synuclein pathology enhances peripheral and CNS immune responses to bacterial endotoxins |
| title_full_unstemmed | Alpha-synuclein pathology enhances peripheral and CNS immune responses to bacterial endotoxins |
| title_short | Alpha-synuclein pathology enhances peripheral and CNS immune responses to bacterial endotoxins |
| title_sort | alpha synuclein pathology enhances peripheral and cns immune responses to bacterial endotoxins |
| topic | Alpha-Synuclein Parkinson's disease Lipopolysaccharide Neurodegenerative disease Neuroinflammation |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003759 |
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