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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• 作者：Shailendra Kumar Maurya ; Juhi Mishra ; Sabiya Abbas…
• 关键词：Pyrethroid ; Growth factor ; NF ; κB ; Astrogliosis ; Neurodegeneration
• 刊名：Molecular Neurobiology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：53
• 期：2
• 页码：968-982
• 全文大小：4,045 KB
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• 作者单位：Shailendra Kumar Maurya (1)
  Juhi Mishra (1)
  Sabiya Abbas (2)
  Sanghamitra Bandyopadhyay (1)
  
  1. Developmental Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India
  2. Food and Chemical Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India
  
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182

文摘

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. Keywords Pyrethroid Growth factor NF-κB Astrogliosis Neurodegeneration