engleski

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

Generation of amyloid- peptides (As) by proteolytic cleavage of the amyloid- protein precursor (APP), especially increased production of A42/A43 over A40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer’s disease (AD). In familial AD (FAD), altered A production originates from specific mutations ofAPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of -secretase. In sporadic AD, the origin of altered production of As remains unknown.We hypothesize that the ‘human chemical exposome’ contains products able to favor the production of A42/A43 over A40 and shorter As. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced A42/A43 production. Nine pyrazole insecticides were found to induce a - and -secretase-dependent, 3-10-fold increase in the production of extracellular A42 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 As cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on - secretase activity, pyrazoles shifted the cleavage pattern of another - secretase substrate, alcadein, and shifted the cleavage of APP by highly purified -secretase toward A42/A43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of A42/A43 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 A42/A43 peptides, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.

A38, A40, A42, A43, A42/A40 ratio, aftins, Alzheimer’s disease, alzheimerogen, amyloid-, amyloid-

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