Voorhees Jaymie R, Remy Matthew T, Erickson Claire M, Dutca Laura M, Brat Daniel J, Pieper Andrew A
1Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA USA.
2Interdisciplinary Graduate Program in Human Toxicology, University of Iowa Graduate College, Iowa City, IA USA.
NPJ Aging Mech Dis. 2019 Jan 22;5:3. doi: 10.1038/s41514-018-0033-3. eCollection 2019.
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.
职业性接触有机磷酸酯类农药，如毒死蜱（CPF），会增加患阿尔茨海默病（AD）的风险，但其机制尚不清楚。为了对此进行研究，我们让4个月大的雄性和雌性野生型（WT）以及转基因AD模型TgF344-AD大鼠，接受一种职业性CPF暴露模式，该模式再现了农业工人所经历的生物标志物和行为损伤。在接下来的20个月里对随后的认知和神经病理学进行了分析。CPF暴露导致雄性和雌性大鼠慢性小胶质细胞失调并加速神经退行性变。对神经退行性变的影响在雄性中更严重，并且还与加速的认知障碍有关。CPF暴露后雌性未表现出加速的认知障碍，并且雄性和雌性的淀粉样蛋白沉积和tau病变均未改变。小胶质细胞失调可能介导了与职业性有机磷酸酯暴露相关的AD风险增加，并且未来旨在维持或恢复正常小胶质细胞的疗法可能有助于预防暴露于CPF或其他加速疾病的环境因素的遗传易感性个体患AD。
