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

Abstract

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 in vivo 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, hAPP Sw=Ind) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil at 0:1 lg=L in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including Ab aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of Ab aggregation in vivo via a longitudinal study using twophoton microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of Ab 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 Ab peptide fibril formation in vitro and involved an in vivo overexpression of the levels of the b-secretasecleaving enzyme (BACE1) combined with impairment of Ab 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 (0:1 lg=L), strengthened the preexisting pathological markers: neuroinflammation, Ab aggregation, and APP b-processing. 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.

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

“…Beyond Aβ production, pesticides could also potentially promote aspects of amyloidogenesis, such as Aβ oligomerization and fibril formation, as well as amyloid plaque formation. Evidence in this regard are scarce, but this possibility has been recently demonstrated by Lafon et al [66], in which the fungicide cocktail of cyprodinil, mepanipyrim, and pyrimethanil associate with amyloid plaques and appears to promote Aβ fibril formation in vitro, as described in more detail in Section 3 above. Rotenone exposure (as low as 0.5 nM) of neuron cultures from rat hippocampus, substantia nigra and locus coeruleus resulted in the formation of protein aggregates of α-Synuclein and Aβ [56].…”

“…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.…”

“…In this regard, a recent report using residual amounts of fungicides in an AD transgenic mouse model is worth noting. Lafon et al [ 66 ] exposed J20 mice (harboring mutant hAPP Sw/Ind ) to a cocktail of 3 fungicides, Cyprodinil, Mepanipyrim, and Pyrimethanil, at a residual dose of 0.1 μg/L in drinking water for 9 months. This resulted in enhanced Aβ aggregation, gliosis, and neuronal loss.…”

“…These were found to induce, in a β- and γ-secretase-dependent manner, an increase in extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells (iPSCs) derived from healthy and familial AD (FAD) patients. Pesticide induction of Aβ usually occurs as a consequence of increases in the expression or activity of BACE1 and γ-secretase [ 59 , 63 , 65 , 66 ], often in combination with a reduction in Aβ clearance due to a suppression of the levels of Aβ-degrading enzymes such as IDE or neprylisin [ 62 , 63 , 66 ]. These pesticides would often also induce an increase in the levels of tau and p-tau [ 57 , 58 , 59 , 61 , 94 ].…”

Fungicide Exposure and Amyloid Plaques in Mice: Further Evidence of an Environmental Risk Factor for Alzheimer’s Disease

“…1 However, these and other environmental risk factors have received limited attention in the study of Alzheimer's disease (AD), 2,3 despite shared disease features. Now, an analysis published in Environmental Health Perspectives 4 reports that chronic exposure to very low doses of certain fungicides promoted pathological changes in a transgenic mouse model of AD.…”