title: Fingolimod Limits Acute Aβ Neurotoxicity and Promotes Synaptic Versus Extrasynaptic NMDA Receptor Functionality in Hippocampal Neurons.
abstract: Fingolimod, also known as FTY720, is an analogue of the sphingolipid sphingosine, which has been proved to be neuroprotective in rodent models of Alzheimer's disease (AD). Several cellular and molecular targets underlying the neuroprotective effects of FTY720 have been recently identified. However, whether the drug directly protects neurons from toxicity of amyloid-beta (Aβ) still remains poorly defined. Using a combination of biochemical assays, live imaging and electrophysiology we demonstrate that FTY720 induces a rapid increase in GLUN2A-containing neuroprotective NMDARs on the surface of dendritic spines in cultured hippocampal neurons. In addition, the drug mobilizes extrasynaptic GLUN2B-containing NMDARs, which are coupled to cell death, to the synapses. Altered ratio of synaptic/extrasynaptic NMDARs decreases calcium responsiveness of neurons to neurotoxic soluble Aβ 1-42 and renders neurons resistant to early alteration of calcium homeostasis. The fast defensive response of FTY720 occurs through a Sphingosine-1-phosphate receptor (S1P-R) -dependent mechanism, as it is lost in the presence of S1P-R1 and S1P-R3 antagonists. We propose that rapid synaptic relocation of NMDARs might have direct impact on amelioration of cognitive performance in transgenic APPswe/PS1dE9 AD mice upon sub-chronic treatment with FTY720.
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089 Rozzano, Italy.
authors.forename: Pooja
authors.initials: P
authors.lastname: Joshi
authors.affiliation: CNR Institute of Neuroscience, via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Gabrielli
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, via Vanvitelli 32, 20129 Milano, Italy.|Fondazione Umberto Veronesi, Milano, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ponzoni
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pelucchi
authors.affiliation: Department of Molecular Biochemistry and Pharmacology IRCSS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20156 Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Stravalaci
authors.affiliation: Department of Molecular Biochemistry and Pharmacology IRCSS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20156 Milan, Italy.
authors.forename: Marten
authors.initials: M
authors.lastname: Beeg
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089 Rozzano, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mazzitelli
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Braida
authors.affiliation: CNR Institute of Neuroscience, via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Mariaelvina
authors.initials: M
authors.lastname: Sala
authors.affiliation: Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Boda
authors.affiliation: Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Buffo
authors.affiliation: Department of Molecular Biochemistry and Pharmacology IRCSS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20156 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089 Rozzano, Italy.|CNR Institute of Neuroscience, via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Marcello
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089 Rozzano, Italy.|CNR Institute of Neuroscience, via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
mesh_terms: D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D002118:Calcium; D000068876:Fingolimod Hydrochloride; D018696:Neuroprotective Agents; D066329:Protein Aggregates; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor