Induction of Amyloid-β₄₂ Production by Fipronil and Other Pyrazole Insecticides

Article type: Research Article

Authors: Cam, Morgane^{a; 1} | Durieu, Emilie^{a; 1} | Bodin, Marion^a | Manousopoulou, Antigoni^b | Koslowski, Svenja^{a; c} | Vasylieva, Natalia^d | Barnych, Bogdan^d | Hammock, Bruce D.^d | Bohl, Bettina^e | Koch, Philipp^{e; f} | Omori, Chiori^{g; h} | Yamamoto, Kazuo^h | Hata, Saori^g | Suzuki, Toshiharu^g | Karg, Frankⁱ | Gizzi, Patrick^j | Erakovic Haber, Vesna^k | Bencetic Mihaljevic, Vlatka^k | Tavcar, Branka^k | Portelius, Erik^l | Pannee, Josef^{l; m} | Blennow, Kaj^{l; m} | Zetterberg, Henrik^{l; m; n; o} | Garbis, Spiros D.^b | Auvray, Pierrick^c | Gerber, Hermeto^{p; q; r} | Fraering, Jeremy^{p; q} | Fraering, Patrick C.^{p; q} | Meijer, Laurent^{a; *}

Affiliations: [a] ManRos Therapeutics, Centre de Perharidy, Roscoff, Bretagne, France | [b] Faculty of Medicine, Cancer Sciences and Clinical and Experimental Medicine, University of Southampton, Southampton, UK | [c] C.RIS Pharma, Parc Technopolitain, Atalante Saint Malo, Saint Malo, France | [d] Department of Entomology and Nematology and UCD Comprehensive Cancer Center, University of California, Davis, CA, USA | [e] Institute of Reconstructive Neurobiology, University of Bonn, Bonn, Germany | [f] Central Institute of Mental Health, University of Heidelberg/ Medical, Faculty Mannheim and Hector Institut for Translational Brain Research (HITBR gGmbH), Mannheim, Germany | [g] Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan | [h] Department of Integrated Bioscience, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Japan | [i] HPC INTERNATIONAL SAS and Atlantis Développement SAS, Noyal-Châtillon sur Seiche, Saint-Erblon, France | [j] Plate-forme TechMedILL, UMR 7242, ESBS - Pôle API, Illkirch cedex, France | [k] Fidelta d.o.o., Zagreb, Croatia | [l] Clinical Neurochemical Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [m] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden | [n] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK | [o] UK Dementia Research Institute, London, UK | [p] Foundation Eclosion, Switzerland | [q] Campus Biotech Innovation Park, Geneva, Switzerland | [r] Department of Biology, University of Fribourg, Fribourg, Switzerland

Correspondence: [*] Correspondence to: Laurent Meijer, ManRos Therapeutics, 29680 Roscoff, France. Tel.: +33 6 08 60 58 34; E-mail: meijer@manros-therapeutics.com.

Note: [1] These authors contributed equally to this work.

Abstract: Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (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 toward 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.

Keywords: Aβ₃₈, Aβ₄₀, Aβ₄₂, Aβ₄₃, Aβ₄₂/Aβ₄₀ ratio, aftins, Alzheimer’s disease, alzheimerogen, amyloid-β, amyloid-β protein precursor, fipronil, γ-secretase, human chemical exposome, pesticides, phenylpyrazoles, prevention, pyrazoles, triazines

DOI: 10.3233/JAD-170875

Journal: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1663-1681, 2018