Induction of Amyloid-β 42 Production by Fipronil and Other Pyrazole Insecticides

Generation of amyloid β peptides (Aβs) by proteolytic cleavage of the amyloid precursor protein (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer’s disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the ‘human chemical exposome’ contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products we screened a library of 3500+ compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazoleinsecticides were found to induce a β- and γ-secretase-dependent, 3-10 fold increase in the production of extracellular Aβ42 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 Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazolesshifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase towards Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronilsulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fiproniladministered orally to mice and rats is known to be metabolized rapidly, mostly to fipronilsulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazoleinsecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.