Fungicide Residues Exposure and Aggregation in a Mouse Model of Alzheimer's Disease.

Background: Pesticide residues have contaminated our environment and nutrition over the last century. Although these compounds are present at very low concentrations, their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer's disease is not clear and difficult to establish. To date, no experiments have yet modeled the impact of this chronic contamination on neurodegenerative disorders.

Objectives: We investigated the impact of fungicide residues on the pathological markers of Alzheimer's disease in a transgenic mouse model.

Methods: Transgenic (J20, ) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil at in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of aggregation via a longitudinal study using two-photon microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of peptides.

Results: We found that a chronic exposure to three fungicide residues exacerbated aggregation, microgliosis, and neuronal loss. These fungicides also increased vascular amyloid aggregates reminiscent of cerebral amyloid angiopathy between 6 and 9 months of treatment. The mechanism of action revealed that fungicides promoted peptide fibril formation and involved an overexpression of the levels of the -cleaving enzyme (BACE1) combined with impairment of clearance through neprylisin (NEP).

Conclusions: Chronic exposure of the J20 mouse model of Alzheimer's disease to a cocktail of fungicides, at the regulatory concentration allowed in tap water (), strengthened the preexisting pathological markers: neuroinflammation, aggregation, and APP . We hypothesize prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer's epidemic. https://doi.org/10.1289/EHP5550.