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Fipronil and Other Pyrazole Insecticides Induce Amyloid-β42 Production

March 7, 2018
Roscoff, France – A new study led by Laurent Meijer of ManRos Therapeutics shows that some pyrazole insecticides, of which fipronil is an archetype, trigger enhanced in vitro production of Aβ42/Aβ43 over Aβ40 amyloid peptides in a cell-free, highly purified preparation of γ-secretase, in various cell lines and in neurons differentiated from human-induced pluripotent stem cells (iPSCs) from a healthy or a familial Alzheimer’s disease (AD) patient with the APP K724N mutation. Findings are published in the Journal of Alzheimer’s Disease.

Immunoprecipitation/mass spectrometry analyses show enhanced production of A peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Pyrazoles also shift the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of these insecticides on γ-secretase activity. Fipronil is metabolized to fipronil sulfone, a very stable metabolite and potent Aβ42/Aβ43 inducer, which accumulates in adipose tissue and brain, suggesting that long-term exposure in animals could lead to Aβ42/Aβ43 production in vivo.

These observations complement similar results obtained with Aftins (FASEB J 26, 5115; JAD 35, 107) and some triazine herbicides (JAD 54, 1593). Thus, several compounds from the human chemical exposome (HCE), which comprise more than 85,000 products, enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, which characterizes AD.

“We have added some pyrazole insecticides, especially the main metabolite of fipronil, in the growing list of HCE products which are able to alter the specificity of Aβ production,” commented Laurent Meijer, PhD, Chairman and Chief Scientific Officer of ManRos Therapeutics, Roscoff, France. “On a long-term, cumulative and additive basis, these compounds may alter the Aβ production pattern sufficiently to lead to AD pathogenesis, suggesting the possible existence of environmental ‘Alzheimerogens’ (named by analogy with carcinogens), which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD. The main metabolite of fipronil, a ‘persistent organic product (POP)’ widely used in agriculture, urban pest control and veterinary applications, stably accumulates in adipose tissue and is able to cross the blood brain barrier, therefore qualifying as a potential Alzheimerogen.”

Identifying compounds able to induce Aβ42/Aβ43 production may provide keys to understand some of the initiating causes of sporadic AD. Furthermore, some of these products might be turned into pharmacological tools to develop non-recombinant, chemically-induced AD animal models.

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NOTES FOR EDITORS
Full study: Morgane Cam, Emilie Durieu, Marion Bodin, Antigoni Manousopoulou, Svenja Koslowski, Natalia Vasylieva, Bogdan Barnych, Bruce D. Hammock, Bettina Bohl, Philipp Koch, Chiori Omori, Kazuo Yamamoto, Saori Hata, Toshiharu Suzuki, Frank Karg, Patrick Gizzi, Vesna Erakovic-Haber, Vlatka Bencetic Mihaljevic, Branka Tavcar, Erik Portelius, Josef Pannee, Kaj Blennow, Henrik Zetterberg, Spiros D. Garbis, Pierrick Auvray, Hermeto Gerber, Jeremy Fraering, Patrick C. Fraering and Laurent Meijer (2018) “Induction of Amyloid-42 Production by Fipronil and Other Pyrazole Insecticides,”  published online in advance in J Alzheimer’s Dis 62 (4) (doi: 10.3233/JAD-170875).

Contact
Laurent Meijer
meijer@manrostherapeutics.com

About ManRos Therapeutics
Founded in 2007 in Roscoff (Brittany, France), ManRos Therapeutics is a spin-off biotech company initiated from a CNRS lab (manros-therapeutics.com). It aims at optimizing, characterizing and bringing low molecular weight, synthetic, pharmacological inhibitors of disease-relevant protein kinases towards clinical trials against cystic fibrosis (Roscovitine, phase 2a clinical trial), polycystic kidney disease (Finisterines, preclinical) and Down syndrome/Alzheimer’s disease (Leucettines, preclinical). Development of new animal models of human disease is also one of the objectives of ManRos Therapeutics.

About the Journal of Alzheimer’s Disease
Celebrating its 20th anniversary in 2018, the Journal of Alzheimer’s Disease (j-alz.com) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease and clinical trial outcomes. The Journal of Alzheimer’s Disease (JAD) has an impact factor of 3.731 according to the 2016 Journal Citation Reports (Clarivate Analytics, 2017). JAD is published by IOS Press (iospress.com).