Fingolimod Limits Acute Aβ Neurotoxicity and Promotes Synaptic Versus Extrasynaptic NMDA Receptor Functionality in Hippocampal Neurons

Pooja Joshi, Martina Gabrielli, Luisa Ponzoni, Silvia Pelucchi, Matteo Stravalaci, Marten Beeg, Sonia Mazzitelli, Daniela Braida, Mariaelvina Sala, Enrica Boda, Annalisa Buffo, Marco Gobbi, Fabrizio Gardoni, Michela Matteoli, Elena Marcello, Claudia Verderio

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number41734
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - Jan 30 2017

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Fingolimod Limits Acute Aβ Neurotoxicity and Promotes Synaptic Versus Extrasynaptic NMDA Receptor Functionality in Hippocampal Neurons'. Together they form a unique fingerprint.

Cite this