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Cypermethrin Stimulates GSK3β-Dependent Aβ and p-tau Proteins and Cognitive Loss in Young Rats: Reduced HB-EGF Signaling and Downstream Neuroinflammation as Critical Regulators

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A Correction to this article was published on 30 August 2019

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Abstract

Pesticide exposure is recognized as a risk factor for Alzheimer’s disease (AD). We investigated early signs of AD-like pathology upon exposure to a pyrethroid pesticide, cypermethrin, reported to impair neurodevelopment. We treated weanling rats with cypermethrin (10 and 25 mg/kg) and detected dose-dependent increase in the key proteins of AD, amyloid beta (Aβ), and phospho-tau, in frontal cortex and hippocampus as early as postnatal day 45. Upregulation of Aβ pathway involved an increase in amyloid precursor protein (APP) and its pro-amyloidogenic processing through beta-secretase (BACE) and gamma-secretase. Tau pathway entailed elevation in tau and glycogen-synthase kinase-3-beta (GSK3β)-dependent, phospho-tau. GSK3β emerged as a molecular link between the two pathways, evident from reduction in phospho-tau as well as BACE upon treating GSK3β inhibitor, lithium chloride. Exploring the mechanism revealed an attenuated heparin-binding epidermal growth factor (HB-EGF) signaling and downstream astrogliosis-mediated neuroinflammation to be responsible for inducing Aβ and phospho-tau. Cypermethrin caused a proximal reduction in HB-EGF, which promoted astrocytic nuclear factor kappa B signaling and astroglial activation close to Aβ and phospho-tau. Glial activation stimulated generation of interleukin-1 (IL-1), which upregulated GSK3β, and APP and tau as well, resulting in co-localization of Aβ and phospho-tau with IL-1 receptor. Intracerebral insertion of exogenous HB-EGF restored its own signaling and suppressed neuroinflammation and thereby Aβ and phospho-tau in cypermethrin-exposed rats, proving a central role of reduced HB-EGF signaling in cypermethrin-mediated neurodegeneration. Furthermore, cypermethrin stimulated cognitive impairments, which could be prevented by exogenous HB-EGF. Our data demonstrate that cypermethrin induces premature upregulation of GSK3β-dependent Aβ and tau pathways, where HB-EGF signaling and neuroinflammation serve as essential regulators.

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Change history

  • 30 August 2019

    The original version of this article unfortunately contained mistakes. The authors noticed that Fig.��1C (cortex), 1D (hippocampus), 4A (cortex), 4B (cortex) and the beta actin Western blot of Supplement 2A in the original article had errors.

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Acknowledgments

Funding from CSIR Network project-INDEPTH and miND are acknowledged. We acknowledge Dr. Debabrata Ghosh, CSIR-IITR, for helping in making Fig. 7; Mr Rajesh Khushwaha for helping in making Figs. 2 and 4; and Dr. Naibedya Chattopadhyay, CSIR-CDRI, for useful suggestions in writing the manuscript.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Developmental Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India

    Shailendra Kumar Maurya, Juhi Mishra & Sanghamitra Bandyopadhyay

  2. Food and Chemical Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India

    Sabiya Abbas

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  1. Shailendra Kumar Maurya
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Suppl. 1

Timeline of treatments. A: To investigate the effect of cypermethrin alone; B: To investigate the role of GSK3β- inhibition (by LiCl) in cypermethrin-treated rats; C: To investigate the effect of exogenous HB-EGF in cypermethrin-treated rats; D: To investigate the effect of IL-1R1-inhibition (by IL-1Ra) in cypermethrin-treated rats. (GIF 30 kb)

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Suppl. 2

LiCL and IL-1Ra suppress GSK3β and IL-1R1. A. Representative western blot and densitometry of GSK3β normalized with β-actin in cortex (LHS) and hippocampus (RHS) of rats treated with cypermethrin and/or LiCl (V= vehicle treated, VL= LiCl + vehicle treated, Cyp= cypermethrin treated and CypL = LiCl + cypermethrin treated). B. Representative western blot and densitometry of IL-1R1 normalized with β-actin in cortex (LHS) and hippocampus (RHS) of rats treated with cypermethrin and/or IL-1Ra (V= vehicle treated, VRa= IL-1Ra + vehicle treated, cyp= cypermethrin treated and cypRa= IL-1Ra + cypermethrin treated). Data represent means ± SE of five rats. ***P<0.001, **P<0.01 and *P<0.05 compared to vehicle (V) or as indicated. (GIF 23 kb)

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Suppl. 3

Cypermethrin induces microglial activation in close proximity of Aβ 1-42 and p-tau. A: Representative photomicrograph (40×-magnification) of microglial marker (Iba-1) (green fluorescence), Aβ1-42 (red fluorescence), nucleus (blue fluorescence), and the three merged in the same field in cortex of cypermethrin-treated rats. B. Representative imunohistochemical photomicrograph of microglial marker (CD68) (red fluorescence), p-tau (green fluorescence), nucleus (blue fluorescence), and the three merged in the same field in cortex of cypermethrin-treated rats. The sections are representatives of five different rats. (GIF 63 kb)

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Suppl. 4

IL-1Ra suppresses Aβ and p-tau. A-B: Representative western blot and densitometry of Aβ1-42 (A) and p-tau (B) normalized with β-actin in cortex (LHS) and hippocampus (RHS) of rats treated with cypermethrinand/or IL-1Ra (V= vehicle treated, VRa= IL-1Ra + vehicle treated, cyp= cypermethrin treated and cypRa= IL-1Ra + cypermethrin treated). Data represent means ± SE of five rats. ***P<0.001, **P<0.01 and *P<0.05 compared to vehicle (V) or as indicated. (GIF 20 kb)

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Suppl. 5

Cypermethrin induces neuronal localization of IL-1R1 and GSK3β. A-B. Representative photomicrograph (40×-magnification) of IL-1R1 (green fluorescence) (A) and GSK3β (green fluorescence) (B), MAP2 (red fluorescence), nucleus (blue fluorescence), and the three merged in the same field. The sections are representatives of five different rats. (GIF 83 kb)

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Maurya, S.K., Mishra, J., Abbas, S. et al. Cypermethrin Stimulates GSK3β-Dependent Aβ and p-tau Proteins and Cognitive Loss in Young Rats: Reduced HB-EGF Signaling and Downstream Neuroinflammation as Critical Regulators. Mol Neurobiol 53, 968–982 (2016). https://doi.org/10.1007/s12035-014-9061-6

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