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.
Dorsal root ganglia (DRG) sensory neurons arise from heterogeneous precursors that differentiate in two neurogenic waves, respectively controlled by Neurog2 and Neurog1. We show here that transgenic mice expressing a Zeb1/2 dominant-negative form (DBZEB) exhibit reduced numbers of nociceptors and altered pain sensitivity. This reflects an early impairment of Neurog1-dependent neurogenesis due to the depletion of specific sensory precursor pools, which is slightly later partially compensated by the contribution of boundary cap cells (BCCs). Indeed, combined DBZEB expression and genetic BCCs ablation entirely deplete second wave precursors and, in turn, nociceptors, thus recapitulating the Neurog1(-/-) neuronal phenotype. Altogether, our results uncover roles for Zeb family members in the developing DRGs; they show that the Neurog1-dependent sensory neurogenesis can be functionally partitioned in two successive phases; and finally, they illustrate plasticity in the developing peripheral somatosensory system supported by the BCCs, thereby providing a rationale for sensory precursor diversity.
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