title: Kisspeptin prevention of amyloid-β peptide neurotoxicity in vitro.
abstract: Alzheimer's disease (AD) onset is associated with changes in hypothalamic-pituitary-gonadal (HPG) function. The 54 amino acid kisspeptin (KP) peptide regulates the HPG axis and alters antioxidant enzyme expression. The Alzheimer's amyloid-β (Aβ) is neurotoxic, and this action can be prevented by the antioxidant enzyme catalase. Here, we examined the effects of KP peptides on the neurotoxicity of Aβ, prion protein (PrP), and amylin (IAPP) peptides. The Aβ, PrP, and IAPP peptides stimulated the release of KP and KP 45-54. The KP peptides inhibited the neurotoxicity of Aβ, PrP, and IAPP peptides, via an action that could not be blocked by kisspeptin-receptor (GPR-54) or neuropeptide FF (NPFF) receptor antagonists. Knockdown of KiSS-1 gene, which encodes the KP peptides, in human neuronal SH-SY5Y cells with siRNA enhanced the toxicity of amyloid peptides, while KiSS-1 overexpression was neuroprotective. A comparison of the catalase and KP sequences identified a similarity between KP residues 42-51 and the region of catalase that binds Aβ. The KP peptides containing residues 45-50 bound Aβ, PrP, and IAPP, inhibited Congo red binding, and were neuroprotective. These results suggest that KP peptides are neuroprotective against Aβ, IAPP, and PrP peptides via a receptor independent action involving direct binding to the amyloid peptides.
authors.affiliation: Department of Human and Health Sciences, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, U.K; Health Sciences Research Centre, University of Roehampton , Holybourne Avenue, London SW15 4JD, U.K. n.milton@westminster.ac.uk
authors.forename: Nathaniel G N
authors.initials: NG
authors.lastname: Milton
authors.forename: Amrutha
authors.initials: A
authors.lastname: Chilumuri
authors.forename: Eridan
authors.initials: E
authors.lastname: Rocha-Ferreira
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Nercessian
authors.forename: Maria
authors.initials: M
authors.lastname: Ashioti
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002374:Catalase / Q000037:antagonists & inhibitors; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D004396:Coloring Agents; D003224:Congo Red; D006801:Humans; D007124:Immunoenzyme Techniques; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects; D007700:Kinetics; D059648:Kisspeptins / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010766:Phosphorylation; D011328:Prions / Q000037:antagonists & inhibitors / Q000633:toxicity; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D059648:Kisspeptins; D009498:Neurotoxins; D011328:Prions; D034741:RNA, Small Interfering; D003224:Congo Red; D002374:Catalase