Specific Triazine Herbicides Induce Amyloid-β42 Production

Abstract

Proteolytic cleavage of the amyloid precursor protein (AβPP) by secretases leads to extracellular release of amyloid β (Aβ) peptides. Increased production of Aβ 42 over Aβ 40 and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark.Identifying products of the 'human chemical exposome' (HCE) able to induce Aβ 42 production may be a key to understand 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 Aβ 42 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 Aβ 40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ 42 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 Aβ 42 /Aβ 43 amyloids, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.

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

“…We speculate that the higher levels of BACE1 may increase b-cleavage of APP and lower levels of NEP may result in a decrease in clearance of amyloid peptides, thus facilitating accumulation of Ab species. Our results are in agreement with a recent study showing the effect of six triazine herbicides on band c-secretases associated with an overproduction of Ab 1-42 peptides on inducible pluripotent stem cells (iPSCs) derived from patients with familial Alzheimer's disease (Portelius et al 2016). Regarding WT mice, no differences were observed in protein expression levels for the different protagonists involved in the amyloid cascade ( Figure 10A-F), possibly explaining why we did not observe the presence of amyloid plaques in WT mice after 9 months of fungicide treatment ( Figure 3A-E).…”

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

“…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.…”

“…Therefore, impaired or attenuated activity of γ‐secretase may increase the generation of Aβ42 in some patients with sporadic AD who do not carry FAD‐linked PSEN1 or PSEN2 gene mutations, although the levels of Aβ42 in CSF are lowered because of Aβ deposition in the brain. Such altered γ‐secretase activity has been observed in sporadic cases [22,38] and can be induced in cells by compounds that inversely modulate γ‐secretase activity [24].…”

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

“…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].…”

“…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.…”