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Fingolimod Limits Acute Aβ Neurotoxicity and Promotes Synaptic Versus Extrasynaptic NMDA Receptor Functionality in Hippocampal Neurons
- Source :
- Scientific Reports
- Publication Year :
- 2017
-
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.
- Subjects :
- 0301 basic medicine
Amyloid
Fingolimod, neurotransmission, excitatory synapses, hippocampal neurons
Dendritic spine
hippocampal neurons
Mice, Transgenic
excitatory synapses
Hippocampal formation
Protein Aggregation, Pathological
Receptors, N-Methyl-D-Aspartate
Neuroprotection
Article
Mice
Protein Aggregates
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Memory
medicine
Animals
neurotransmission
Receptor
Amyloid beta-Peptides
Multidisciplinary
Sphingosine
Fingolimod Hydrochloride
Chemistry
Pyramidal Cells
Cell Membrane
Neurotoxicity
Fingolimod
medicine.disease
Neuroprotective Agents
030104 developmental biology
nervous system
Anesthesia
Synapses
NMDA receptor
Calcium
Neuroscience
030217 neurology & neurosurgery
Protein Binding
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....7b1988e9e95b79a290d10aa7efbfca82