title: Prokineticin system modulation as a new target to counteract the amyloid beta toxicity induced by glutamatergic alterations in an in vitro model of Alzheimer's disease.
abstract: The accumulation of β-amyloid (Aβ) is one of the hallmarks of Alzheimer disease (AD). Beyond the inflammatory reactions promoted by Aβ, it has been demonstrated that the prokineticin (PK) system, composed of the chemokine prokineticin 2 (PK2) and its receptors, is involved in Aβ toxicity. In this study we have analyzed how the Aβ chronic treatment affects the glutamatergic transmission on neurons from primary cortical cultures, clearly demonstrating the PK system involvement on its action mechanism. In fact, we have observed a significant increase of the ionic current through the AMPA receptors in primary cortical neurons and an up-regulation of the PK system in cultures chronically treated with Aβ. All effects were nullified by the prokineticin antagonist PC-1. Moreover, we have herein firstly demonstrated that the incubation of primary cortical culture with Bv8, the amphibian homologue of PK2, was able to increase in neurons the AMPA currents at specific doses and exposure times, measured both as evoked and as spontaneous currents. This effect was not due to a modification of the AMPA receptor subunit expression. In contrast, the up-modulation of AMPA currents were blocked by PC-1 and were mediated by the activation of the intracellular protein kinase C (PKC) transduction pathways because Gö6983, the PKC inhibitor added in the medium, nullified the effect. Finally, cellular death induced by kainate was also reduced following treatment with PC1. In conclusion, our results show that the prokineticin system may be a key mediator in the Aβ-induced neuronal damage, suggesting PK antagonists as new therapeutic compounds to ameliorate the AD progression.
authors.affiliation: IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Caioli
authors.affiliation: Institute of Cell Biology and Neurobiology, CNR, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Severini
authors.affiliation: European Brain Research Institute, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ciotti
authors.affiliation: European Brain Research Institute, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Florenzano
authors.affiliation: IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Pimpinella
authors.affiliation: Institute of Cell Biology and Neurobiology, CNR, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Petrocchi Passeri
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale, 72, 09124 Cagliari, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier, 1, 00144 Rome, Italy.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Polisca
authors.affiliation: Department of Human Physiology and Pharmacology "Vittorio Erspamer", University of Roma "La Sapienza", P.za A. Moro 5, 00185 Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lattanzi
authors.affiliation: European Brain Research Institute, Via del Fosso di Fiorano, 64, 00143 Rome, Italy; Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica, 1, 00133 Rome, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.affiliation: Department of Human Physiology and Pharmacology "Vittorio Erspamer", University of Roma "La Sapienza", P.za A. Moro 5, 00185 Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Negri
authors.affiliation: IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier, 1, 00133 Rome, Italy. Electronic address: zona@uniroma2.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Zona
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D029845:Amphibian Proteins / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001001:Anura; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005768:Gastrointestinal Hormones / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D029845:Amphibian Proteins; D016229:Amyloid beta-Peptides; C121344:Bv8 protein, Bombina variegata; D005768:Gastrointestinal Hormones; D007211:Indoles; D008301:Maleimides; D009479:Neuropeptides; D018696:Neuroprotective Agents; C470838:PROKR2 protein, human; D047428:Protein Kinase Inhibitors; D018091:Receptors, AMPA; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D018698:Glutamic Acid; D011493:Protein Kinase C
keywords: Amyloid beta; Electrophysiology; Glutamatergic neurotransmission; Prokineticin system