title: Specific Triazine Herbicides Induce Amyloid-β42 Production.
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.
authors: Clinical Neurochemical Laboratory, Institute of Neuroscience & Physiology, University of Gothenburg, Göteborg, Sweden.
authors: Erik
authors: E
authors: Portelius
authors: ManRos Therapeutics, Centre de Perharidy, Roscoff, France.
authors: Emilie
authors: E
authors: Durieu
authors: ManRos Therapeutics, Centre de Perharidy, Roscoff, France.
authors: Marion
authors: M
authors: Bodin
authors: ManRos Therapeutics, Centre de Perharidy, Roscoff, France.
authors: Morgane
authors: M
authors: Cam
authors: Clinical Neurochemical Laboratory, Institute of Neuroscience & Physiology, University of Gothenburg, Göteborg, Sweden.
authors: Josef
authors: J
authors: Pannee
authors: Service de Pharmacologie et d'Immunoanalyse, IBITECS, CEA, Université Paris-Saclay, F-91191 Gif-sur-Yvette Cedex, France.
authors: Charlotte
authors: C
authors: Leuxe
authors: Service de Pharmacologie et d'Immunoanalyse, IBITECS, CEA, Université Paris-Saclay, F-91191 Gif-sur-Yvette Cedex, France.
authors: Aloϊse
authors: A
authors: Mabondzo
authors: ManRos Therapeutics, Centre de Perharidy, Roscoff, France.
authors: Nassima
authors: N
authors: Oumata
authors: ManRos Therapeutics, Centre de Perharidy, Roscoff, France.|Laboratoire de Pharmacochimie, INSERM U1022, Université Paris-Descartes, Paris, France.
authors: Hervé
authors: H
authors: Galons
authors: Department of Chemistry, National University of Singapore, Laboratory of Bioimaging Probe Development, Biopolis, Singapore.
authors: Jung Yeol
authors: JY
authors: Lee
authors: Department of Chemistry, National University of Singapore, Laboratory of Bioimaging Probe Development, Biopolis, Singapore.
authors: Young-Tae
authors: YT
authors: Chang
authors: Institute of Reconstructive Neurobiology, University of Bonn, Bonn, Germany.
authors: Kathrin
authors: K
authors: Stϋber
authors: Institute of Reconstructive Neurobiology, University of Bonn, Bonn, Germany.
authors: Philipp
authors: P
authors: Koch
authors: Sorbonne Universités, UPMC Université Paris 06 UMR S1127, Inserm U1127, CNRS UMR7225, ICM, Paris, France.
authors: Gaëlle
authors: G
authors: Fontaine
authors: Sorbonne Universités, UPMC Université Paris 06 UMR S1127, Inserm U1127, CNRS UMR7225, ICM, Paris, France.
authors: Marie-Claude
authors: MC
authors: Potier
authors: Center for Proteomic Research, Institute for Life Sciences, Cancer and Clinical Experimental Science Units, School of Medicine, University of Southampton, Southampton, UK.
authors: Antigoni
authors: A
authors: Manousopoulou
authors: Center for Proteomic Research, Institute for Life Sciences, Cancer and Clinical Experimental Science Units, School of Medicine, University of Southampton, Southampton, UK.
authors: Spiros D
authors: SD
authors: Garbis
authors: Toxicological Center, University of Antwerp, Wilrijk, Belgium.
authors: Adrian
authors: A
authors: Covaci
authors: Laboratory of Neurochemistry & Behaviour, Department of Biomedical Sciences, Institute Born-Bunge, Wilrijk, Belgium.|University of Groningen, University Medical Center Groningen, Department of Neurology & Alzheimer Research Center, Groningen, The Netherlands.
authors: Debby
authors: D
authors: Van Dam
authors: Laboratory of Neurochemistry & Behaviour, Department of Biomedical Sciences, Institute Born-Bunge, Wilrijk, Belgium.|University of Groningen, University Medical Center Groningen, Department of Neurology & Alzheimer Research Center, Groningen, The Netherlands.
authors: Peter
authors: P
authors: De Deyn
authors: HPC INTERNATIONAL SAS, Noyal-Châtillon sur Seiche, Saint-Erblon, France.
authors: Frank
authors: F
authors: Karg
authors: Laboratory of Molecular & Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors: Marc
authors: M
authors: Flajolet
authors: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors: Chiori
authors: C
authors: Omori
authors: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors: Saori
authors: S
authors: Hata
authors: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors: Toshiharu
authors: T
authors: Suzuki
authors: Clinical Neurochemical Laboratory, Institute of Neuroscience & Physiology, University of Gothenburg, Göteborg, Sweden.
authors: Kaj
authors: K
authors: Blennow
authors: Clinical Neurochemical Laboratory, Institute of Neuroscience & Physiology, University of Gothenburg, Göteborg, Sweden.|UCL Institute of Neurology, London, UK.
authors: Henrik
authors: H
authors: Zetterberg
authors: ManRos Therapeutics, Centre de Perharidy, Roscoff, France.
authors: Laurent
authors: L
authors: Meijer
mesh_terms: D000328:Adult; D016229:Amyloid beta-Peptides / Q000819:agonists / Q000096:biosynthesis*; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D057809:HEK293 Cells; D006540:Herbicides / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010446:Peptide Fragments / Q000819:agonists / Q000096:biosynthesis*; D051381:Rats; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D006540:Herbicides; D010446:Peptide Fragments; D014227:Triazines; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; Aβ42/Aβ40 ratio; alzheimerogen; amyloid-β; amyloid-β protein precursor; herbicides; human chemical exposome; triazines