Specific Triazine Herbicides Induce Amyloid-β42 Production

Proteolytic cleavage of the amyloid-? protein precursor (A?PP) by secretases leads to extracellular release of amyloid-? (A?) peptides. Increased production of A?42 over A?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?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?42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a ?- and ?-secretases-dependent, 2–10 fold increase in the production of extracellular A?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? 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 (A?PP K724N) produced more A?42 versus A?40 than neurons derived from healthy controls iPSCs (A?PP WT). Triazines enhanced A?42 production in both control and AD neurons. Triazines also shifted the cleavage pattern of alcadein?, another ?-secretase substrate, suggesting a direct effect of triazines on ?-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone A?42/A?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.