Dataset Information

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

ABSTRACT: Generation of amyloid-? peptides (A?s) by proteolytic cleavage of the amyloid-? protein precursor (A?PP), especially increased production of A?42/A?43 over A?40, 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 of A?PP or presenilins 1/2 (PS1/PS2), the catalytic subunits of ?-secretase. In sporadic AD, the origin of altered production of A?s remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of A?42/A?43 over A?40 and shorter A?s. To detect such products, we screened a library of 3500?+?compounds in a cell-based assay for enhanced A?42/A?43 production. Nine pyrazole insecticides were found to induce a ?- and ?-secretase-dependent, 3-10-fold increase in the production of extracellular A?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?s 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 A?PP by highly purified ?-secretase toward A?42/A?43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of A?42/A?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?42/A?43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.

SUBMITTER: Cam M

PROVIDER: S-EPMC7065497 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Cam Morgane M Durieu Emilie E Bodin Marion M Manousopoulou Antigoni A Koslowski Svenja S Vasylieva Natalia N Barnych Bogdan B Hammock Bruce D BD Bohl Bettina B Koch Philipp P Omori Chiori C Yamamoto Kazuo K Hata Saori S Suzuki Toshiharu T Karg Frank F Gizzi Patrick P Erakovic Haber Vesna V Bencetic Mihaljevic Vlatka V Tavcar Branka B Portelius Erik E Pannee Josef J Blennow Kaj K Zetterberg Henrik H Garbis Spiros D SD Auvray Pierrick P Gerber Hermeto H Fraering Jeremy J Fraering Patrick C PC Meijer Laurent L

Journal of Alzheimer's disease : JAD 20180101 4

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 unknow ...[more]

PMID: 29504531

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Project description:ImportancePlasma measurement of amyloid-β (Aβ) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce.ObjectiveTo investigate the associations between plasma Aβ42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns.Design, setting, and participantsThis multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020.ExposurePlasma Aβ42 and Aβ40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of Aβ assessment was defined as the baseline for this study.Main outcomes and measuresCognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study-Activities of Daily Living. Mixed-effect linear regressions were performed.ResultsA total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma Aβ42/40 (≤0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ε4 genotype, and MAPT intervention groups, low plasma Aβ42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: -0.20, 95% CI, -0.34 to -0.07; P = .004) and decline in MMSE score (adjusted between-group mean difference: -0.59; 95% CI, -1.07 to -0.11; P = .02) during the follow-up period compared with the group with an Aβ42/40 ratio greater than 0.107.Conclusions and relevanceIn this study, low plasma Aβ42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma Aβ42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement.

Project description:Insecticide resistance poses many challenges in insect pest control, particularly in the control of destructive pests such as red imported fire ants (Solenopsis invicta). In recent years, beta-cypermethrin and fipronil have been extensively used to manage invasive ants, but their effects on resistance development in S. invicta are still unknown. To investigate resistance development, S. invicta was collected from populations in five different cities in Guangdong, China. The results showed 105.71- and 2.98-fold higher resistance against fipronil and beta-cypermethrin, respectively, in the Guangzhou population. The enzymatic activities of acetylcholinesterase, carboxylases, and glutathione S-transferases significantly increased with increasing beta-cypermethrin and fipronil concentrations. Transcriptomic analysis revealed 117 differentially expressed genes (DEGs) in the BC-ck vs. BC-30 treatments (39 upregulated and 78 downregulated), 109 DEGs in F-ck vs. F-30 (33 upregulated and 76 downregulated), and 499 DEGs in BC-30 vs. F-30 (312 upregulated and 187 downregulated). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that DEGs associated with insecticide resistance were significantly enriched in metabolic pathways, the AMPK signaling pathway, the insulin signaling pathway, carbon metabolism, peroxisomes, fatty acid metabolism, drug metabolism enzymes and the metabolism of xenobiotics by cytochrome P450. Furthermore, we found that DEGs important for insecticide detoxification pathways were differentially regulated under both insecticide treatments in S. invicta. Comprehensive transcriptomic data confirmed that detoxification enzymes play a significant role in insecticide detoxification and resistance development in S. invicta in Guangdong Province. Numerous identified insecticide-related genes, GO terms, and KEGG pathways indicated the resistance of S. invicta workers to both insecticides. Importantly, this transcriptome profile variability serves as a starting point for future research on insecticide risk evaluation and the molecular mechanism of insecticide detoxification in invasive red imported fire ants.

Dataset Information

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

Publications

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

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