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

Cam, Morgane; Durieu, Emilie; Bodin, Marion; Manousopoulou, Antigoni; Koslowski, Svenja; Vasylieva, Natalia; Barnych, Bogdan; Hammock, Bruce D.; Bohl, Bettina; Koch, Philipp; Omori, Chiori; Yamamoto, Kazuo; Hata, Satoshi; Suzuki, Toshiharu; Karg, Frank; Gizzi, Patrick; Haber, Vesna Eraković; Mihaljević, Vlatka Bencetić; Tavčar, Branka; Portelius, Erik; Pannee, Josef; Blennow, Kaj; Zetterberg, Henrik; Garbis, Spiros D.; Auvray, Pierrı̈ck; Gerber, Hermeto; Fraering, Jeremy; Fraering, Patrick C.; Meijer, Laurent

doi:10.3233/jad-170875

Cited by 26 publications

(18 citation statements)

References 105 publications

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“…the γ‐site) as has been observed for the APP [21,23]. This alteration is detectable as an endophenotype of p3‐Alcα with C‐terminal variants in patients with AD [22] and in cells treated with compounds that modulate γ‐secretase activity [24,25]. These lines of evidence suggest that the function and metabolism of Alcs are also closely involved in AD pathobiology.…”

Section: Introductionmentioning

confidence: 74%

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

Hata

Omori

Kimura

et al. 2019

A&D Transl Res & Clin Interv

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IntroductionNeuronal p3-Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α- and γ-secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3-Alcβ is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets.MethodsWe developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF).ResultsIn monkeys, CSF p3-Alcβ decreases with age, and the aging is also accompanied by decreased brain expression of Alcβ. In humans, CSF p3-Alcβ levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcβ level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcβ37 while increasing the production of Aβ42.DiscussionAging decreases the generation of p3-Alcβ, and further significant decrease of p3-Alcβ caused by aberrant γ-secretase activity may accelerate pathogenesis in AD.

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Section: Introductionmentioning

confidence: 74%

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

Hata

Omori

Kimura

et al. 2019

A&D Transl Res & Clin Interv

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“…However, our results showed that these doses, on the long term, are deleterious in a transgenic mouse model of Alzheimer's disease. Cypro, mepa, and pyri could be considered Alzheimerogen pollutants (Cam et al 2018;Portelius et al 2016) at the subnanomolar regulatory levels (0:1 lg=L) because they accelerated fibrils formation and promoted the progression of disease's markers in the J20 mouse model. We hypothesize that prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer's epidemic.…”

Section: Discussionmentioning

confidence: 99%

Fungicide Residues Exposure and β-amyloid Aggregation in a Mouse Model of Alzheimer’s Disease

Lafon

Wang

Arango-Lievano

et al. 2020

Environ Health Perspect

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BACKGROUND: Pesticide residues have contaminated our environment and nutrition over the last century. Although these compounds are present at very low concentrations, their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer's disease is not clear and difficult to establish. To date, no in vivo experiments have yet modeled the impact of this chronic contamination on neurodegenerative disorders. OBJECTIVES: We investigated the impact of fungicide residues on the pathological markers of Alzheimer's disease in a transgenic mouse model. METHODS: Transgenic (J20, hAPP Sw=Ind) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil at 0:1 lg=L in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including Ab aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of Ab aggregation in vivo via a longitudinal study using twophoton microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of Ab peptides. RESULTS: We found that a chronic exposure to three fungicide residues exacerbated aggregation, microgliosis, and neuronal loss. These fungicides also increased vascular amyloid aggregates reminiscent of cerebral amyloid angiopathy between 6 and 9 months of treatment. The mechanism of action revealed that fungicides promoted Ab peptide fibril formation in vitro and involved an in vivo overexpression of the levels of the b-secretasecleaving enzyme (BACE1) combined with impairment of Ab clearance through neprylisin (NEP). CONCLUSIONS: Chronic exposure of the J20 mouse model of Alzheimer's disease to a cocktail of fungicides, at the regulatory concentration allowed in tap water (0:1 lg=L), strengthened the preexisting pathological markers: neuroinflammation, Ab aggregation, and APP b-processing. We hypothesize prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer's epidemic.

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“…DDT also increases Aβ levels in H4 glioma cells with a APP Swe transgene via elevation of APP and BACE1, while decreasing the levels of Aβ-clearing ATP-binding cassette transporter A1 (ABCA1) and inhibiting the activity of Aβ-degrading insulin-degrading enzyme (IDE) [63]. Aβ production has also been shown to be elevated by triazine herbicides [64] and pyrazole insecticides in various cell lines [65].…”

Section: Pesticides and The Induction Of Alzheimer's Disease Markers mentioning

confidence: 99%

“…A range of pesticides may act in a manner that is termed by Cam and colleagues as environmental "Alzheimerogens' [65], namely by elevating the levels of Aβ [59,[61][62][63][64][65][66]. The authors screened a large compound library using a cell-based assay for enhanced production of the longer Aβ peptides (Aβ42/Aβ43), and identified 9 pyrazole insecticides.…”

Section: Enhancement Of Aβ and Tau Expression Modification And Clearmentioning

confidence: 99%

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

Tang

2020

Toxics

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Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer’s disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides’ induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.

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

Cited by 26 publications

References 105 publications

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

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

Fungicide Residues Exposure and β-amyloid Aggregation in a Mouse Model of Alzheimer’s Disease

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

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