title: Vitamin D3protects against Aβ peptide cytotoxicity in differentiated human neuroblastoma SH- SY5Y cells: A role for S1P1/p38MAPK/ATF4 axis.
abstract: Besides its classical function of bone metabolism regulation, 1alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3), acts on a variety of tissues including the nervous system, where the hormone plays an important role as neuroprotective, antiproliferating and differentiating agent. Sphingolipids are bioactive lipids that play critical and complex roles in regulating cell fate. In the present paper we have investigated whether sphingolipids are involved in the protective action of 1,25(OH)2D3.We have found that 1,25(OH)2D3prevents amyloid-β peptide (Aβ(1-42)) cytotoxicity both in differentiated SH-SY5Y human neuroblastoma cells and in vivo. In differentiated SH-SY5Y cells, Aβ(1-42) strongly reduces the sphingosine-1-phosphate (S1P)/ceramide (Cer) ratio while 1,25(OH)2D3partially reverts this effect. 1,25(OH)2D3reverts also the Aβ(1-42)-induced reduction of sphingosine kinase activity. We have also studied the crosstalk between 1,25(OH)2D3and S1P signaling pathways downstream to the activation of S1P receptor subtype S1P1. Notably, we found that 1,25(OH)2D3prevents the reduction of S1P1 expression promoted by Aβ(1-42) and thereby it modulates the downstream signaling leading to ER stress damage (p38MAPK/ATF4). Similar effects were observed by using ZK191784. In addition, chronic treatment with 1,25(OH)2D3protects from aggregated Aβ(1-42)-induced damage in the CA1 region of the rat hippocampus and promotes cell proliferation in the hippocampal dentate gyrus of adult mice. In conclusion, these results represent the first evidence of the role of 1,25(OH)2D3and its structural analogue ZK191784 in counteracting the Aβ(1-42) peptide-induced toxicity through the modulation of S1P/S1P1/p38MAPK/ATF4 pathway in differentiated SH-SY5Y cells.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Molecular and Applied Biology Research Unit, University of Florence, Viale GB Morgagni 50, 5134 Firenze, Italy; Interuniversitary Miology Institutes, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Pierucci
authors.affiliation: Department of Biology, University of Pisa, Via San Zen, 31, 56127 Pisa, Italy; Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Via del Borghetto 80, 56124 Pisa, Italy.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Garcia-Gil
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Molecular and Applied Biology Research Unit, University of Florence, Viale GB Morgagni 50, 5134 Firenze, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Frati
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Molecular and Applied Biology Research Unit, University of Florence, Viale GB Morgagni 50, 5134 Firenze, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bini
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Molecular and Applied Biology Research Unit, University of Florence, Viale GB Morgagni 50, 5134 Firenze, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Martinesi
authors.affiliation: Neuroscience Institute, CNR, 56124 Pisa, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Vannini
authors.affiliation: Neuroscience Institute, CNR, 56124 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mainardi
authors.affiliation: Department of Life Sciences and Systems Biology, University of Turin, Neuroscience Institute Cavalier Ottolenghi, Via Verdi 8, 10124 Turin, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Luzzati
authors.affiliation: Department of Life Sciences and Systems Biology, University of Turin, Neuroscience Institute Cavalier Ottolenghi, Via Verdi 8, 10124 Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Peretto
authors.affiliation: Neuroscience Institute, CNR, 56124 Pisa, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Caleo
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Molecular and Applied Biology Research Unit, University of Florence, Viale GB Morgagni 50, 5134 Firenze, Italy; Interuniversitary Miology Institutes, Italy. Electronic address: elisabetta.meacci@unifi.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Meacci
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity*; D020318:Rats, Long-Evans; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002518:Ceramides; D008246:Lysophospholipids; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D049349:Receptors, Lysosphingolipid; C470666:ZK 191784; C075222:amyloid beta-protein (1-42); C065576:ceramide 1-phosphate; D051701:Activating Transcription Factor 4; C060506:sphingosine 1-phosphate; D048051:p38 Mitogen-Activated Protein Kinases; D002117:Calcitriol; D013110:Sphingosine
keywords: ATF4; Ceramide; ER stress; SH-SY5Y cells; Sphingosine 1-phosphate; Vitamin D; p38 MAPK; β-amyloid peptide