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Induction of amyloid-β42 production by fipronil and other pyrazole insecticides

Induction of amyloid-β42 production by fipronil and other pyrazole insecticides
Induction of amyloid-β42 production by fipronil and other pyrazole insecticides
Generation of amyloid β peptides (Aβs) by proteolytic cleavage of the amyloid precursor protein (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer’s disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the ‘human chemical exposome’ contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products we screened a library of 3500+ compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10 fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase towards Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.
1387-2877
1663-1681
Cam, Morgane
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Durieu, Emilie
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Bodin, Marion
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Manousopoulou, Antigoni
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Koslowski, Svenja
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Vasylieva, Natalia
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Barnych, Bogdan
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Hammock, Bruce D.
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McMahen, Rebecca L.
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Strynar, Mark J.
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Bohl, Bettina
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Koch, Philipp
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Omori, Chiori
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Yamamoto, Kazuo
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Hata, Saori
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Suzuki, Toshiharu
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Karg, Frank
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Gizzi, Patrick
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Erakovic-Haber, Vesna
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Mihaeljevic, Vlatka Bencetic
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Tavcar, Branka
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Portelius, Erik
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Pannee, Josef
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Blennow, Kaj
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Zetterberg, Henrik
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Garbis, Spiros
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Auvray, Pierrick
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Gerber, Hermeto
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Fraering, Jeremy
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Fraering, Patrick
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Meijer, Laurent
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Cam, Morgane
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Durieu, Emilie
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Bodin, Marion
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Manousopoulou, Antigoni
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Koslowski, Svenja
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Vasylieva, Natalia
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Barnych, Bogdan
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Hammock, Bruce D.
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McMahen, Rebecca L.
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Strynar, Mark J.
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Koch, Philipp
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Hata, Saori
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Suzuki, Toshiharu
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Karg, Frank
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Gizzi, Patrick
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Erakovic-Haber, Vesna
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Mihaeljevic, Vlatka Bencetic
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Tavcar, Branka
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Portelius, Erik
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Pannee, Josef
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Blennow, Kaj
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Zetterberg, Henrik
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Garbis, Spiros
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Auvray, Pierrick
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Gerber, Hermeto
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Fraering, Jeremy
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Fraering, Patrick
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Meijer, Laurent
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Cam, Morgane, Durieu, Emilie, Bodin, Marion, Manousopoulou, Antigoni, Koslowski, Svenja, Vasylieva, Natalia, Barnych, Bogdan, Hammock, Bruce D., McMahen, Rebecca L., Strynar, Mark J., Bohl, Bettina, Koch, Philipp, Omori, Chiori, Yamamoto, Kazuo, Hata, Saori, Suzuki, Toshiharu, Karg, Frank, Gizzi, Patrick, Erakovic-Haber, Vesna, Mihaeljevic, Vlatka Bencetic, Tavcar, Branka, Portelius, Erik, Pannee, Josef, Blennow, Kaj, Zetterberg, Henrik, Garbis, Spiros, Auvray, Pierrick, Gerber, Hermeto, Fraering, Jeremy, Fraering, Patrick and Meijer, Laurent (2018) Induction of amyloid-β42 production by fipronil and other pyrazole insecticides. Journal of Alzheimer's Disease, 1663-1681. (doi:10.3233/JAD-170875).

Record type: Article

Abstract

Generation of amyloid β peptides (Aβs) by proteolytic cleavage of the amyloid precursor protein (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer’s disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the ‘human chemical exposome’ contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products we screened a library of 3500+ compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10 fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase towards Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.

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Induction_of_amyloid_42_production_by_fipronil_and_other_pyrazole_insecticides_J_Alz_Dis_2018_Text - Accepted Manuscript
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Accepted/In Press date: 8 January 2018
e-pub ahead of print date: 27 March 2018

Identifiers

Local EPrints ID: 417758
URI: https://eprints.soton.ac.uk/id/eprint/417758
ISSN: 1387-2877
PURE UUID: ce766295-4e06-4501-b994-6358deafd1b0

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Date deposited: 13 Feb 2018 17:30
Last modified: 14 Mar 2019 05:16

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Contributors

Author: Morgane Cam
Author: Emilie Durieu
Author: Marion Bodin
Author: Antigoni Manousopoulou
Author: Svenja Koslowski
Author: Natalia Vasylieva
Author: Bogdan Barnych
Author: Bruce D. Hammock
Author: Rebecca L. McMahen
Author: Mark J. Strynar
Author: Bettina Bohl
Author: Philipp Koch
Author: Chiori Omori
Author: Kazuo Yamamoto
Author: Saori Hata
Author: Toshiharu Suzuki
Author: Frank Karg
Author: Patrick Gizzi
Author: Vesna Erakovic-Haber
Author: Vlatka Bencetic Mihaeljevic
Author: Branka Tavcar
Author: Erik Portelius
Author: Josef Pannee
Author: Kaj Blennow
Author: Henrik Zetterberg
Author: Spiros Garbis
Author: Pierrick Auvray
Author: Hermeto Gerber
Author: Jeremy Fraering
Author: Patrick Fraering
Author: Laurent Meijer

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