Abstract Title:

Specific Triazine Herbicides Induce Amyloid-β42 Production.

Abstract Source:

J Alzheimers Dis. 2016 Oct 18 ;54(4):1593-1605. PMID: 27589520

Abstract Author(s):

Erik Portelius, Emilie Durieu, Marion Bodin, Morgane Cam, Josef Pannee, Charlotte Leuxe, Aloϊse Mabondzo, Nassima Oumata, Hervé Galons, Jung Yeol Lee, Young-Tae Chang, Kathrin Stϋber, Philipp Koch, Gaëlle Fontaine, Marie-Claude Potier, Antigoni Manousopoulou, Spiros D Garbis, Adrian Covaci, Debby Van Dam, Peter De Deyn, Frank Karg, Marc Flajolet, Chiori Omori, Saori Hata, Toshiharu Suzuki, Kaj Blennow, Henrik Zetterberg, Laurent Meijer

Article Affiliation:

Erik Portelius


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 aβ- 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 (AβPPWT). 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.

Study Type : Human In Vitro

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