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

Sci Rep. 2017 Jan 30:7:41734. doi: 10.1038/srep41734.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Calcium / metabolism
  • Cell Membrane / metabolism
  • Fingolimod Hydrochloride / pharmacology
  • Memory / drug effects
  • Mice
  • Mice, Transgenic
  • Neuroprotective Agents / pharmacology
  • Protein Aggregates
  • Protein Aggregation, Pathological
  • Protein Binding
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synapses / metabolism*

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • NR2B NMDA receptor
  • Neuroprotective Agents
  • Protein Aggregates
  • Receptors, N-Methyl-D-Aspartate
  • Fingolimod Hydrochloride
  • Calcium
  • N-methyl D-aspartate receptor subtype 2A