Amyloid β Peptide Levels Increase in Brain of AβPP Swedish Mice after Exposure to Chlorpyrifos

Abstract

Chlorpyrifos (CPF) is an organophosphate pesticide widely used in intensive agriculture. Various studies have demonstrated delayed neurotoxic effects in adult mammals after acute CPF exposure. This pesticide induces oxidative stress and neuronal damage, which suggests a possible relationship between CPF exposure and Alzheimer's disease (AD). In the present study, we examined in a mice model of AD, long-term changes in the behavior and brain levels of amyloid β after acute CPF exposure. Fifty mg/kg of CPF were subcutaneously injected to Tg2576 (Tg) mice carrying the Swedish amyloid-β protein precursor (AβPP) mutation for AD. General status, body weight, acetyl cholinesterase (AChE) inhibition, and behavioral changes were assessed. Amyloid β fragment (1-40 and 1-42) levels were also measured in the cortical and hippocampal brain regions. A significant and transient decrease in body weight was observed 72 hr after treatment, while no autonomic effects were noted. Motor activity was decreased in Tg mice seven months after CPF treatment. Acquisition learning in a water maze task was not affected, but retention was ameliorated in CPF-exposed Tg mice. Amyloid β levels increased in the brains of treated Tg mice eight months after CPF exposure. The results of this study show that some behavioral changes persisted or emerged months after acute CPF exposure, while amyloid β levels increased. These findings raise concern about the risk of developing neurodegenerative diseases following moderate exposure to CPF in vulnerable subjects.

Chronic exposure to chlorpyrifos triggered body weight increase and memory impairment depending on human apoE polymorphisms in a targeted replacement mouse model

“…Our present investigation reveals that chronic oral exposure to CPF increased the search velocity in these subjects, which may explain their apparent improvement. In animal models, activity after adult exposure to CPF has been reported to either increase [51] or decrease [63] in Tg2576 mice. In a recent study, increased vertical activity and a trend towards an anxiety trait were observed five months after repeated exposure to CPF in Tg2576 adult male mice [51].…”

“…To date numerous studies have endorsed the neurotoxic and behavioral effects of CPF in both human [6,20,21,55,62] and animal models [10,37,40,63,67]. CPF exerts its insecticidal activity by irreversibly inhibiting cholinesterases (ChE) and disrupting cholinergic function in the nervous system.…”

Acute and long-term exposure to chlorpyrifos induces cell death of basal forebrain cholinergic neurons through AChE variants alteration

“…In this regard, previous in vitro studies have shown that muscarinic agonists (primarily M1 and M3, but also M4) promote cell survival (Budd et al, 2003(Budd et al, , 2004De Sarno et al, 2003;Lindenboim et al, 1995). Besides, CPF has been described to increase Ab protein production (Salazar et al, 2011), tau and GSK-3b hyperphosphorilation (Chen et al, 2012;Torres-Altoro et al, 2011), both having been related with induction of cell death in basal forebrain cholinergic neurons and AD (Kar et al, 2004), and also for being able to mediate this effect. Moreover, CPF also is able to induce reactive oxygen species (ROS) formation (Ki et al, 2013), and they Fig.…”

Effects of Detraining on Ach, AchE, β-amyloid, Apolipoprotein Expression and Cognitive Function in Brain Tissue of Memory Impairment Rats

“…Several in vitro studies have documented that dichlorodiphenyltrichloroethane (DDT) significantly increases levels of amyloid-β precursor protein (Aβ PP) and β -site Aβ PP-cleaving enzyme 1(BACE1), impairing the clearance and extracellular degradation of amyloid-β peptides 28,29 . An in vivo study revealed that some pesticides may disrupt metabolic pathways involved in the homeostasis of amyloid-β , causing a significant increase in amyloid-β levels in the cortex and hippocampus, as well as increased memory loss and reduced motor activity in experimental animals 30 . Thus, some researchers have hypothesized that pesticide exposure is a potential risk factor for AD, and this hypothesis has been further validated by the results of several epidemiological studies 12,18 .…”