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.
The interaction of genes and environment contributes to Alzheimer’s disease (AD). For example, agricultural workers, military personnel, industrial manufacturers, veterinarians, horticulturists, aircraft maintenance personnel, and pilots are all potentially at risk of occupational exposure to organophosphates (OPs), which are associated with increased risk of AD. We report here that occupational-like exposure of young animals to the OP chlorpyrifos (CPF) accelerates AD-like cognitive deficits and severe neurodegeneration in male, but not female, TgF344-AD rats, a genetic model of AD. CPF exposure also causes chronic dysregulation of brain microglial cells, while amyloid and tau pathology are not affected. Thus, microglial dysregulation after environmental toxin exposure may represent a second hit that advances the disease. 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.