Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides

Generation of amyloid-beta peptides (A beta s) by proteolytic cleavage of the amyloid-beta protein precursor (A beta PP), especially increased production of A beta(42)/A beta(43) over A beta(40), and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered A beta production originates from specific mutations of A beta PP or presenilins 1/2 (PS1/PS2), the catalytic subunits of gamma-secretase. In sporadic AD, the origin of altered production of A beta s remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of A beta(42)/A beta(43) over A beta(40) and shorter A beta s. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced A beta(42)/A beta(43) production. Nine pyrazole insecticides were found to induce a beta- and gamma-secretase-dependent, 3-10-fold increase in the production of extracellular A beta(42) in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of A beta s cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on gamma-secretase activity, pyrazoles shifted the cleavage pattern of another gamma-secretase substrate, alcadein alpha, and shifted the cleavage of A beta PP by highly purified gamma-secretase toward A beta(42)/A beta(43). Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of A beta(42)/A beta(43) in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone A beta(42)/A beta(43) peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.