Specific Triazine Herbicides Induce Amyloid-beta(42) Production

Abstract

Proteolytic cleavage of the amyloid-beta protein precursor (A beta PP) ecretases leads to extracellular release of amyloid-beta (A beta) peptides. Increased production of A beta(42) over A beta(40) and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifying products of the 'human chemical exposome' (HCE) able to induce A beta(42) 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 A beta(42) inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a beta- and gamma-secretases-dependent, 2-10 fold increase in the production of extracellular A beta(42) 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 A beta 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 familialAD(FAD) patient (A beta PP K724N) produced more A beta(42) versus A beta(40) than neurons derived from healthy controls iPSCs (A beta PP WT). Triazines enhanced A beta(42) production in both control and AD iPSCs-derived neurons. Triazines also shifted the cleavage pattern of alcadein alpha, another gamma-secretase substrate, suggesting a direct effect of triazines on gamma-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone A beta(42)/A beta(43) amyloids, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.