Elsevier

Neurobiology of Aging

Volume 33, Issue 2, February 2012, Pages 432.e15-432.e26
Neurobiology of Aging

Abstract of online article
Cognitive impairment and increased Aβ levels induced by paraquat exposure are attenuated by enhanced removal of mitochondrial H2O2

https://doi.org/10.1016/j.neurobiolaging.2011.01.008Get rights and content

Abstract

Pesticide exposure is a risk factor of Alzheimer's disease (AD). However, little is known about how pesticide exposure may promote AD pathogenesis. In this study, we investigated the effects of paraquat pesticide exposure on β-amyloid (Aβ) levels and cognition using wild-type (WT) mice and β-amyloid precursor protein (APP) transgenic mice. Our results showed that wild-type mice and APP transgenic mice after paraquat exposure had increased oxidative damage specifically in mitochondria of cerebral cortex and exhibited mitochondrial dysfunction. Moreover, the elevated mitochondrial damage was directly correlated with impaired associative learning and memory and increased Aβ levels in APP transgenic mice exposed to paraquat. Furthermore, overexpression of peroxiredoxin 3, a mitochondrial antioxidant defense enzyme important for H2O2 removal, protected against paraquat-induced mitochondrial damage and concomitantly improved cognition and decreased Aβ levels in APP transgenic mice. Therefore, our results demonstrate that mitochondrial damage is a key mechanism underlying cognitive impairment and elevated amyloidogenesis induced by paraquat and that enhanced removal of mitochondrial H2O2 could be an effective strategy to ameliorate AD pathogenesis induced by pesticide exposure.

Introduction

Alzheimer's disease (AD) is the most common dementia affecting millions of people around the world. AD is classified into 2 categories: familial AD and sporadic AD. Familial AD is early onset and makes up a small portion of total AD cases (Tanzi and Bertram, 2005). The vast majority of AD is sporadic and late onset. Despite extensive research, the pathogenic mechanisms of sporadic AD remain unclear. However, accumulating evidence indicates that the etiology of sporadic AD involves interactions between genetic factors and environmental factors (Landrigan et al., 2005), and exposure to toxins such as pesticides was found to increase the risk of AD by several epidemiological studies (Baldi et al., 2003, Hayden et al., 2010, Santibanez et al., 2007). Although epidemiological data indicate that pesticide exposure is a risk factor of AD (Baldi et al., 2003, Hayden et al., 2010), experimental data showing a causal relationship between pesticide exposure and AD is lacking, and little is known about how pesticide exposure may affect AD pathogenesis. Paraquat is a widely used herbicide around the world. Paraquat exposure was shown to elevate the risk of Parkinson's disease (Costello et al., 2009), and paraquat exposure is used extensively for studying disease mechanisms of Parkinson's disease (McCormack et al., 2005). Although paraquat preferentially affects the nigrostriatum system, it is known to accumulate in cerebral cortex and hippocampus (Prasad et al., 2009). Therefore, paraquat could potentially impair learning and memory and affect AD pathogenesis. The major toxicity mechanism of paraquat exposure is the induction of oxidative stress and mitochondrial damage, a common toxicity mechanism elicited by many environmental toxins and pesticides (Drechsel and Patel, 2008). Oxidative stress and mitochondrial dysfunction are also believed to play a pivotal role in the pathogenesis of AD (Lin and Beal, 2006). Therefore, experimental models of paraquat exposure could be useful not only for validating the role of pesticide exposure in AD pathogenesis but also for studying the disease mechanisms of AD.

H2O2 is a reactive oxygen species (ROS) important for inducing oxidative damage and regulating redox-sensitive signaling (Rhee, 2006). Under normal conditions, the majority of cellular H2O2 is produced by mitochondria. Increased mitochondrial H2O2 generation was implicated to be important for AD pathogenesis (Du et al., 2008, Manczak et al., 2006). Moreover, paraquat was shown to enhance H2O2 production by brain mitochondria (Castello et al., 2007). However, the potential role of mitochondrial H2O2 in the elevated risk of AD induced by pesticide exposure has not been investigated. Peroxiredoxin 3 (PRDX3) is a member of the peroxiredoxin family that is localized exclusively in mitochondria and is believed to play a major role in mitochondrial H2O2 removal (Cox et al., 2010). We previously generated transgenic mice overexpressing PRDX3, and showed that brain mitochondria from PRDX3 transgenic mice had significantly decreased H2O2 generation (Chen et al., 2008b). Therefore, PRDX3 transgenic mice are useful models to study the importance of mitochondrial H2O2 in affecting pesticide-induced AD pathogenesis.

In this study, we examined cognition and Aβ levels in β-amyloid precursor protein (APP) transgenic mice and non-APP transgenic mice exposed to paraquat. Our results indicate that paraquat exposure exacerbates cognitive impairment and elevates Aβ levels primarily by inducing mitochondrial damage, and that reduction of mitochondrial H2O2 by overexpression of PRDX3 attenuates cognitive impairment and amyloidogenesis induced by paraquat exposure.

Section snippets

Animals and paraquat exposure

The generation of transgenic mice overexpressing PRDX3 [Tg(PRDX3) mice] was previously described (Chen et al., 2008b). Tg(PRDX3) mice were bred with C57BL/6 mice, and male offspring wild-type (WT) mice and Tg(PRDX3) (TG) mice were used in the studies.

APP transgenic mice (Tg2576 mice) were obtained from Taconic (Taconic, NY, USA). Male Tg2576 mice were used to cross with female Tg(PRDX3) mice, offspring mice with the APP transgene but without the PRDX3 transgene were designated as APP/WT mice,

Mitochondrial damage in cerebral cortex of paraquat-exposed WT mice and the rescue by PRDX3 overexpression

To investigate the effects of paraquat on brain regions important for cognition such as the cerebral cortex, we exposed WT mice (3–4 months of age) to paraquat using a chronic exposure protocol, in which each mouse received 6 injections of paraquat (intraperitoneal) over a period of 3 weeks at a relatively low dose of 10 mg/kg. Because paraquat caused oxidative stress in dopaminergic neurons (McCormack et al., 2005, Prasad et al., 2007), we first looked at the markers of oxidative stress in the

Discussion

Exposure to environmental toxins such as pesticides is shown to be a risk factor of AD (Santibanez et al., 2007). In this study, we studied the effect of paraquat exposure on cognition and amyloidogenesis, and investigated the mechanism that may be responsible for the heightened risk of AD. Our study provided several new insights into the role of pesticide exposure in AD pathogenesis.

First, our results demonstrate that exposure to paraquat, a widely used pesticide, exacerbates AD phenotypes in

Disclosure statement

The authors declare no conflict of interest.

All procedures for handling the mice in this study were reviewed and approved by the Institutional Animal Care and Use Committees of the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System.

Acknowledgements

The study was supported by a Merit Award (QR) from the Department of Veteran Affairs.

References (34)

  • L. Chen et al.

    Reduction of mitochondrial H2O2 by overexpressing peroxiredoxin 3 improves glucose tolerance in mice

    Aging Cell

    (2008)
  • P.E. Coskun et al.

    Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • S. Costello et al.

    Parkinson's disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California

    Am. J. Epidemiol

    (2009)
  • A.G. Cox et al.

    Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling

    Biochem. J

    (2010)
  • H. Du et al.

    Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease

    Nat. Med

    (2008)
  • D.A. Gallo et al.

    Associative recognition in Alzheimer's disease: evidence for impaired recall-to-reject

    Neuropsychology

    (2004)
  • J. Hardy et al.

    The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics

    Science

    (2002)
  • Cited by (52)

    • Mitochondrial response to environmental toxicants

      2021, Mitochondrial Metabolism: An Approach to Disease Management
    View all citing articles on Scopus
    View full text