title: 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.
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.
authors.affiliation: Developmental Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India.
authors.forename: Shailendra Kumar
authors.initials: SK
authors.lastname: Maurya
authors.affiliation: Developmental Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India.
authors.forename: Juhi
authors.initials: J
authors.lastname: Mishra
authors.affiliation: Food and Chemical Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India.
authors.forename: Sabiya
authors.initials: S
authors.lastname: Abbas
authors.affiliation: Developmental Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India. sanghmitra@iitr.res.in.
authors.forename: Sanghamitra
authors.initials: S
authors.lastname: Bandyopadhyay
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000473:pathology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008568:Memory / Q000187:drug effects; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011722:Pyrethrins / Q000633:toxicity*; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D066257:Heparin-binding EGF-like Growth Factor; D016328:NF-kappa B; D011722:Pyrethrins; D016875:tau Proteins; C017160:cypermethrin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Astrogliosis; Growth factor; NF-κB; Neurodegeneration; Pyrethroid