Occupational exposure to organophosphate pesticides, such as chlorpyrifos (CPF), increases the risk of Alzheimer’s disease (AD), though the mechanism is unclear. To investigate this, we subjected 4-month-old male and female wild-type (WT) and TgF344-AD rats, a transgenic AD model, to an occupational CPF exposure paradigm that recapitulates biomarkers and behavioral impairments experienced by agricultural workers. Subsequent cognition and neuropathology were analyzed over the next 20 months. CPF exposure caused chronic microglial dysregulation and accelerated neurodegeneration in both males and females. The effect on neurodegeneration was more severe in males, and was also associated with accelerated cognitive impairment. Females did not exhibit accelerated cognitive impairment after CPF exposure, and amyloid deposition and tauopathy were unchanged in both males and females. Microglial dysregulation may mediate the increased risk of AD associated with occupational organophosphate exposure, and future therapies to preserve or restore normal microglia might help prevent AD in genetically vulnerable individuals exposed to CPF or other disease-accelerating environmental agents.

尽管机理尚不清楚，但职业接触有机磷农药（如毒死rif（CPF））会增加患阿尔茨海默氏病（AD）的风险。为了对此进行调查，我们对4个月大的雄性和雌性野生型（WT）和TgF344-AD大鼠（一种转基因AD模型）进行了职业CPF暴露范式，该范式概括了生物标志物和农业工人的行为障碍。在接下来的20个月中分析了随后的认知和神经病理学。CPF暴露导致男性和女性的慢性小胶质细胞失调，并加速神经变性。男性对神经退行性的影响更为严重，并且还与加速的认知障碍有关。女性在CPF暴露后没有表现出加速的认知障碍，男性和女性的淀粉样蛋白沉积和tauopathy均未改变。小胶质细胞失调可能会介导与职业性有机磷酸酯暴露相关的AD风险增加，并且将来用于保存或恢复正常小胶质细胞的疗法可能有助于预防暴露于CPF或其他疾病加速环境因素的遗传脆弱个体的AD。