Influence of chlorpyrifos oxon on the development and progression of Alzheimer′s disease in amyloid precursor protein transgenic mice

Abstract

Aim: Alzheimer's disease (AD) is a devastating neurological disorder and the most common form of dementia. Until date, the cause of AD eludes us, but a number of hypotheses have been put forward to try and understand the mechanisms involved. A series of studies have indicated that environmental factors, such as pesticides, heavy metals, and others can contribute to the development and progression of AD. Based on these data, we determined the impact of pesticides (chlorpyrifos oxon [CPO]) on AD-like pathogenesis in amyloid precursor protein (APP) transgenic mice. Methods: APP mice were treated at various times with low-dose CPO (1 mg/kg/day), in utero (3-week of gestation), during lactation (3-week), or as young adults (continuous dosing). Results: Exposure to CPO at all times enhanced neuro-inflammation and exacerbated oxidative stress in the brain prior to amyloid deposition. CPO-treated APP mice showed a decrease in memory and learning compared with untreated APP mice; furthermore, analyses of brain tissue sections and extracts showed an increase in Ab levels and C-terminal fragment-b levels, a decrease in soluble APPa (sAPPa) levels, and an increase in plaque load. In addition, CPO-treated APP transgenic mice showed a significant decrease in neurotrophic factor levels (nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3) compared to vehicle-treated APP transgenic animals. Treatment with galantamine attenuated the effects of CPO by reducing amyloid b levels and amyloid load. Conclusion: CPO accelerated and exacerbated the disease development and progression in the APP mice suggesting that pesticides may play a significant role in the pathogenesis of AD.