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Original Article

Influence of chlorpyrifos oxon on the

development and progression of Alzheimer’s

disease in amyloid precursor protein transgenic

mice

Jin Yu , Hong Zhu , Aruna Bhat , Hanaa El-Sayed , Tatyana Gudz , Sebastiano Gattoni-Celli ,
1,4
1,2
1,4
1,4
1,4
2,3
Mark S. Kindy 1,2,4
1 Departments of Regenerative Medicine and Cell Biology and Neurosciences, Medical University of South Carolina, Charleston,
SC 29425, USA.
2 Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29425, USA.
3 Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA.
4 Department of Bioengineering, Clemson University, Clemson, SC 29634, USA.
ABSTRA CT

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 Aβ levels and C‑terminal fragment‑β levels, a decrease in
soluble APPα (sAPPα) 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 β 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.

Key words: Amyloid beta, Alzheimer’s disease, amyloid, cognition, inflammation, toxin

INTRODUCTION proteolysis of its precursor, the amyloid precursor
protein (APP). [2,3] In addition, a variety of neuronal
Amyloid β peptide (Aβ) containing senile plaques are cytoskeletal alterations is prominent features of AD
one of the neuropathological hallmarks of Alzheimer’s neuropathology. [4,5] Whether these abnormal features are
disease (AD). Much of this work has focused on the result or cause of neuronal loss is still controversial.
the biosynthesis of Aβ and factors that influence its [6-10] Early onset autosomal dominant AD is directly
deposition. The Aβ peptides are generated via internal linked to mutations in one of the several genes: APP,
[1]
presenilin 1 (PS1), or presenilin 2 (PS2). [11-13] In
Access this article online addition, several genes, most notably the apolipoprotein
Quick Response Code: E (APOE) 4 allele, alter risk for later onset AD, and it is
Website: clear that mutation or polymorphism in several other
www.nnjournal.net
genes can lead to similar AD phenotypes. [14]
DOI:
10.4103/2347-8659.149421 Recent studies have suggested that early exposure of
individuals to environmental toxins, drugs, and other

Corresponding Author: Dr. Mark S. Kindy, Departments of Regenerative Medicine and Cell Biology and Neurosciences, Medical
University of South Carolina, Strom Thurmond Research Building, 114 Doughty Street, Room 503, Charleston, SC 29425, USA.
E‑mail: kindyms@musc.edu

Neuroimmunol Neuroinflammation | Volume 2 | Issue 1 | January 15, 2015 31