Till sidans topp

Sidansvarig: Webbredaktion
Sidan uppdaterades: 2012-09-11 15:12

Tipsa en vän
Utskriftsversion

Induction of Amyloid-β42 … - Göteborgs universitet Till startsida
Webbkarta
Till innehåll Läs mer om hur kakor används på gu.se

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

Artikel i vetenskaplig tidskrift
Författare 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
Laurent Meijer
Publicerad i Journal of Alzheimer's disease : JAD
Volym 62
Nummer/häfte 4
Sidor 1663-1681
ISSN 1875-8908
Publiceringsår 2018
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Sidor 1663-1681
Språk en
Länkar dx.doi.org/10.3233/JAD-170875
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämnesord Aβ38, Aβ40, Aβ42, Aβ43, Aβ42/Aβ40 ratio, aftins, Alzheimer’s disease, alzheimerogen, amyloid-β, amyloid-β protein precursor, fipronil, γ-secretase, human chemical exposome, pesticides, phenylpyrazoles, prevention, pyrazoles, triazines
Ämneskategorier Neurokemi

Sammanfattning

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.

Sidansvarig: Webbredaktion|Sidan uppdaterades: 2012-09-11
Dela:

På Göteborgs universitet använder vi kakor (cookies) för att webbplatsen ska fungera på ett bra sätt för dig. Genom att surfa vidare godkänner du att vi använder kakor.  Vad är kakor?