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Göteborgs universitets publikationer

Specific Triazine Herbicides Induce Amyloid-β42 Production.

Författare och institution:
Erik Portelius (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Emilie Durieu (-); Marion Bodin (-); Morgane Cam (-); Josef Pannee (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Charlotte Leuxe (-); Aloϊse Mabondzo (-); Nassima Oumata (-); Hervé Galons (-); Jung Yeol Lee (-); Young-Tae Chang (-); Kathrin Stϋber (-); Philipp Koch (-); Gaëlle Fontaine (-); Marie-Claude Potier (-); Antigoni Manousopoulou (-); Spiros Garbis (-); Adrian Covaci (-); Debby Van Dam (-); Peter De Deyn (-); Frank Karg (-); Marc Flajolet (-); Chiori Omori (-); Saori Hata (-); Toshiharu Suzuki (-); Kaj Blennow (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Henrik Zetterberg (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Laurent Meijer (-)
Publicerad i:
Journal of Alzheimer's disease : JAD,
Artikel, refereegranskad vetenskaplig
Sammanfattning (abstract):
Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifying products of the 'human chemical exposome' (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a β- and γ-secretases-dependent, 2-10 fold increase in the production of extracellular Aβ42 in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familial AD (FAD) patient (AβPP K724N) produced more Aβ42 versus Aβ40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ42 production in both control and AD neurons. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Medicinska grundvetenskaper ->
Neurovetenskaper ->
Postens nummer:
Posten skapad:
2016-09-06 18:15

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