Specific Triazine Herbicides Induce Amyloid-β42 Production

Area of Science:

• Neuroscience
• Toxicology
• Biochemistry

Background:

• Alzheimer's disease (AD) is characterized by increased amyloid-beta 42 (Aβ42) over Aβ40 production and aggregation.
• The human chemical exposome (HCE) may contain environmental factors initiating AD.
• Identifying Aβ42 inducers is crucial for understanding AD causes and developing animal models.

Purpose of the Study:

• To screen HCE libraries for compounds that induce Aβ42 production.
• To investigate the mechanism of Aβ42 induction by identified compounds.
• To explore the potential role of environmental factors in AD pathogenesis.

Main Methods:

• Screening of HCE libraries using a cell model for Aβ42 induction.
• Treatment of various cell lines, primary neurons, and iPSC-derived neurons with identified compounds.
• Immunoprecipitation/mass spectrometry to analyze Aβ peptide cleavage patterns.
• Analysis of γ-secretase substrate (alcadeinα) cleavage shifts.

Main Results:

• Six triazine herbicides were identified as inducers of Aβ42 production (2-10 fold increase).
• Triazines enhanced Aβ42 production in both control and familial AD patient-derived iPSC neurons.
• Triazines altered Aβ cleavage patterns, favoring Aβ42/Aβ43 production, characteristic of AD.
• Triazines affected alcadeinα cleavage, suggesting direct impact on γ-secretase activity.

Conclusions:

• Widely used triazine herbicides enhance the production of toxic, aggregation-prone Aβ42/Aβ43 amyloids.
• Environmental "Alzheimerogens" may contribute to the initiation and propagation of amyloidogenesis in late-onset AD.
• These findings highlight potential environmental triggers for Alzheimer's disease.