No abstract

Proteolytic cleavage of the amyloid precursor protein (AβPP) by secretases leads to extracellular release of amyloid β (Aβ) peptides. Increased production of Aβ 42 over Aβ 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 Aβ 42 production may be a key to understand 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 Aβ 42 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 Aβ 40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ 42 production in both control and AD 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 Aβ 42 /Aβ 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.