Fungicide Residues Exposure and β-amyloid Aggregation in a Mouse Model of Alzheimer’s Disease

Autor: Laurent Givalois, Margarita Arango-Lievano, Josep V. Mercader, Marine Mansuy, Freddy Jeanneteau, Lucie Salvador-Prince, Catherine Desrumaux, Joan Torrent, Nadine Mestre-Francés, Pierre-André Lafon, Véronique Perrier, Jianfeng Liu, Yunyun Wang
Přispěvatelé: Perrier, Véronique, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellular Signaling Laboratory [Hubei, China] (College of Life Science and Technology), Huazhong University of Science and Technology [Wuhan] (HUST), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institute of Agrochemistry and Food Technology (IATA), Instituto de Agroquímica y Tecnología de Alimentos - Institute of Agrochemistry and Food Technology [Valencia] (IATA-CSIC), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), This project was supported by the French government under the Programme d’investissement d’Avenir, Initiative SciencesInnovation Territoire–MUSE (Montpellier University Site of Excellence) with reference ANR-16-IDEX-0006, I-Site MUSE STEMPest. This project was supported by grants from the French National Research Agency (ANR) under the program Investissement d’Avenir with reference ANR-11-LABX-0021-LipSTIC. W.Y. is the recipient of a fellowship from the China Scholar ship Council under the Programme Hubert Curien (PHC) CAI YUANPEI 2014-16–project no. 32106RD and a joint-PhD student from Huazhong University of Science and Technology and University of Montpellier. P.A.L. is the recipient of a fellowship from the French Ministry o fHigher Education and Research and from the Center of Excellence for Neurodegenerative diseases of Montpellier (CoEN)–CHU of Montpellier certified by AVIESAN as part of the Plan maladies neurodégénératives (2014–2019)., Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Sino-France Laboratory for Drug Screening, Laboratoire de recherches de la chaire de génétique, Institut National de la Recherche Agronomique (INRA), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Agence Nationale de la Recherche (France)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Health
Toxicology and Mutagenesis
Transgene
Plaque
Amyloid
Disease
010501 environmental sciences
01 natural sciences
Microbiology
03 medical and health sciences
Mice
0302 clinical medicine
β amyloid
Alzheimer Disease
Risk Factors
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
medicine
Animals
030212 general & internal medicine
Volume concentration
ComputingMilieux_MISCELLANEOUS
0105 earth and related environmental sciences
biology
Pesticide residue
Chemistry
Research
Public Health
Environmental and Occupational Health
medicine.disease
3. Good health
Fungicides
Industrial
Fungicide
13. Climate action
biology.protein
[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Alzheimer's disease
Amyloid precursor protein secretase
Zdroj: Environmental Health Perspectives
Environmental Health Perspectives, 2020, 128 (1), pp.017011. ⟨10.1289/EHP5550⟩
Environmental Health Perspectives, National Institute of Environmental Health Sciences, 2020, 128 (1), pp.017011. ⟨10.1289/EHP5550⟩
Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 0091-6765
1552-9924
Popis: Background: Pesticide residues have contaminated our environment and nutrition over the last century. Although these compounds are present at very low concentrations, their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer’s disease is not clear and difficult to establish. To date, no in vivo experiments have yet modeled the impact of this chronic contamination on neurodegenerative disorders. Objectives: We investigated the impact of fungicide residues on the pathological markers of Alzheimer’s disease in a transgenic mouse model. Methods: Transgenic (J20, hAPPSw/Ind ) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil at 0.1μg/L in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including Aβ aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of Aβ aggregation in vivo via a longitudinal study using two-photon microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of Aβ peptides. Results: We found that a chronic exposure to three fungicide residues exacerbated aggregation, microgliosis, and neuronal loss. These fungicides also increased vascular amyloid aggregates reminiscent of cerebral amyloid angiopathy between 6 and 9 months of treatment. The mechanism of action revealed that fungicides promoted Aβ peptide fibril formation in vitro and involved an in vivo overexpression of the levels of the β-secretase–cleaving enzyme (BACE1) combined with impairment of Aβ clearance through neprylisin (NEP). Conclusions: Chronic exposure of the J20 mouse model of Alzheimer’s disease to a cocktail of fungicides, at the regulatory concentration allowed in tap water (0.1μg/L ), strengthened the preexisting pathological markers: neuroinflammation, Aβ aggregation, and APP β-processing. We hypothesize prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer’s epidemic.
This project was supported by the French government under the Programme d’investissement d’Avenir, Initiative Sciences Innovation Territoire–MUSE (Montpellier University Site of Excellence) with reference ANR-16-IDEX-0006, I-Site MUSE STEMPest. This project was supported by grants from the French National Research Agency (ANR) under the program Investissement d’Avenir with reference ANR-11-LABX-0021-LipSTIC. W.Y. is the recipient of a fellowship from the China Scholarship Council under the Programme Hubert Curien (PHC) CAI YUANPEI 2014-16–project no. 32106RD and a joint-PhD student from Huazhong University of Science and Technology and University of Montpellier. P.A.L. is the recipient of a fellowship from the French Ministry of Higher Education and Research and from the Center of Excellence for Neurodegenerative diseases of Montpellier (CoEN)–CHU of Montpellier certified by AVIESAN as part of the Plan maladies neuro-dégénératives (2014–2019).
Databáze: OpenAIRE
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