ArticleJournal of Alzheimer's disease : JAD2018
Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides.
Article in Journal of Alzheimer's disease : JAD, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 29 citations in OpenAlex.
- Restoring amyloid-β42 and γ-secretase function in Alzheimer's disease.Brain : a journal of neurology · 2025Review
- Fipronil Triggers Immunotoxicity Through Reactive Oxygen Species-Driven Mitochondrial Apoptosis in Thymocytes.Toxics · 2025Article
- Induction of Thymus Atrophy and Disruption of Thymocyte Development by Fipronil through Dysregulation of IL-7-Associated Genes.Chemical research in toxicology · 2024Article
- Fipronil disturbs the antigen-specific immune responses and GABAergic gene expression in the ovalbumin-immunized BALB/c mice.BMC veterinary research · 2024Article
- The Association between Pesticide Exposure and the Development of Fronto-Temporal Dementia-Cum-Dissociative Disorders: A Review.Brain sciences · 2023Review
- Chronic Administration of Fipronil Heterogeneously Alters the Neurochemistry of Monoaminergic Systems in the Rat Brain.International journal of molecular sciences · 2020Article
- Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of alcadein α-deficient mice.The Journal of biological chemistry · 2020Article
- Article
- Long-Term Fipronil Treatment Induces Hyperactivity in Female Mice.International journal of environmental research and public health · 2020Article
- Fungicide Residues Exposure andEnvironmental health perspectives · 2020Article
- Neurotoxicity of pesticides.Acta neuropathologica · 2019Review
- Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants.International journal of genomics · 2019Review
- Decrease in p3-Alcβ37 and p3-Alcβ40, products of Alcadein β generated by γ-secretase cleavages, in aged monkeys and patients with Alzheimer's disease.Alzheimer's & dementia (New York, N. Y.) · 2019Article
Corrections and comments
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Authors and funding
29 authors at 12 institutions in 7 countries.
Funding
Abstract
Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (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 presenilins 1/2 (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 pyrazole insecticides 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, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 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 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.
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