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. 2016 Mar;53(2):968-982. doi: 10.1007/s12035-014-9061-6. Epub 2015 Jan 10.


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: Astrogliosis; Growth factor; NF-κB; Neurodegeneration; Pyrethroid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / pathology*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cognition Disorders / metabolism*
  • Cognition Disorders / pathology
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Heparin-binding EGF-like Growth Factor / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Male
  • Memory / drug effects
  • Models, Biological
  • NF-kappa B / metabolism
  • Phosphorylation
  • Pyrethrins / toxicity*
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects
  • tau Proteins / metabolism*


  • Amyloid
  • Amyloid beta-Peptides
  • Heparin-binding EGF-like Growth Factor
  • NF-kappa B
  • Pyrethrins
  • tau Proteins
  • cypermethrin
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3