Portelius, E;
Durieu, E;
Bodin, M;
Cam, M;
Pannee, J;
Leuxe, C;
Mabondzo, A;
... Meijer, L; + view all
(2016)
Specific triazine herbicides induce amyloid β42 production.
Journal of Alzheimer's Disease
, 54
(4)
pp. 1593-1605.
10.3233/JAD-160310.
Preview |
Text
Zetterberg_Portelius.pdf - Accepted Version Download (311kB) | Preview |
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 iPSCs-derived 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.
| Type: | Article |
|---|---|
| Title: | Specific triazine herbicides induce amyloid β42 production |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3233/JAD-160310 |
| Publisher version: | http://doi.org/10.3233/JAD-160310 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Alzheimer’s disease, alzheimerogen, amyloid-β, amyloid-β protein precursor, Aβ42/Aβ40 ratio, herbicides, human chemical exposome, triazines, SPORADIC ALZHEIMERS-DISEASE, GAMMA-SECRETASE ACTIVITY, CELL-DERIVED NEURONS, AMYLOID-BETA, CEREBROSPINAL-FLUID, STEM-CELL, OCCUPATIONAL-EXPOSURE, INDUSTRIAL-CHEMICALS, IN-VITRO, EXPOSOME |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1538364 |
Archive Staff Only
 |
View Item |
