Specific Triazine Herbicides Induce Amyloid-β₄₂ Production

Article type: Research Article

Authors: Portelius, Erik^a | Durieu, Emilie^b | Bodin, Marion^b | Cam, Morgane^b | Pannee, Josef^a | Leuxe, Charlotte^c | Mabondzo, Aloϊse^c | Oumata, Nassima^b | Galons, Hervé^{b; d} | Lee, Jung Yeol^e | Chang, Young-Tae^e | Stϋber, Kathrin^f | Koch, Philipp^f | Fontaine, Gaëlle^g | Potier, Marie-Claude^g | Manousopoulou, Antigoni^h | Garbis, Spiros D.^h | Covaci, Adrianⁱ | Van Dam, Debby^{j; k} | De Deyn, Peter^{j; k} | Karg, Frank^l | Flajolet, Marc^m | Omori, Chioriⁿ | Hata, Saoriⁿ | Suzuki, Toshiharuⁿ | Blennow, Kaj^a | Zetterberg, Henrik^{a; o} | Meijer, Laurent^{b; *}

Affiliations: [a] Clinical Neurochemical Laboratory, Institute of Neuroscience & Physiology, University of Gothenburg, Göteborg, Sweden | [b] ManRos Therapeutics, Centre de Perharidy, Roscoff, France | [c] Service de Pharmacologie et d’Immunoanalyse, IBITECS, CEA, Université Paris-Saclay, F-91191 Gif-sur-Yvette Cedex, France | [d] Laboratoire de Pharmacochimie, INSERM U1022, Université Paris-Descartes, Paris, France | [e] Department of Chemistry, National University of Singapore, Laboratory of Bioimaging Probe Development, Biopolis, Singapore | [f] Institute of Reconstructive Neurobiology, University of Bonn, Bonn, Germany | [g] Sorbonne Universités, UPMC Université Paris 06 UMR S1127, Inserm U1127, CNRS UMR7225, ICM, Paris, France | [h] Center for Proteomic Research, Institute for Life Sciences, Cancer and Clinical Experimental Science Units, School of Medicine, University of Southampton, Southampton, UK | [i] Toxicological Center, University of Antwerp, Wilrijk, Belgium | [j] Laboratory of Neurochemistry & Behaviour, Department of Biomedical Sciences, Institute Born-Bunge, Wilrijk, Belgium | [k] University of Groningen, University Medical Center Groningen, Department of Neurology & Alzheimer Research Center, Groningen, The Netherlands | [l] HPC INTERNATIONAL SAS, Noyal-Châtillon sur Seiche, Saint-Erblon, France | [m] Laboratory of Molecular & Cellular Neuroscience, The Rockefeller University, New York, NY, USA | [n] Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan | [o] UCL Institute of Neurology, London, UK

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

Abstract: Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer’s disease (AD) hallmark. Identifying products of the ‘human chemical exposome’ (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a β- and γ-secretases-dependent, 2–10 fold increase in the production of extracellular Aβ42 in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familial AD (FAD) patient (AβPP K724N) produced more Aβ42 versus Aβ40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ42 production in both control and AD iPSCs-derived neurons. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.

Keywords: Alzheimer’s disease, alzheimerogen, amyloid-β, amyloid-β protein precursor, Aβ₄₂/Aβ₄₀ ratio, herbicides, human chemical exposome, triazines

DOI: 10.3233/JAD-160310

Journal: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1593-1605, 2016