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.
Highlights
While molecular mechanisms mediating neurotoxicity of soluble tau forms largely remain to be elucidated, glutamate ionotropic NMDA receptors (NMDARs) have emerged as specific targets of soluble Aβ1–42 (s-Aβ) oligomers
Consistent with a therapeutic action of FTY720, in the nest building task, there was an improvement of nest building score in APPswe/PS1dE9 mice compared to corresponding vehicle-treated group (Supplementary Fig. 1E)
Our study strongly suggests a mechanistic link between neuroprotective effects of Fingolimod against Aβ–induced neurodegeneration and rapid relocation of functional NMDARs in cultured hippocampal neurons
Summary
While molecular mechanisms mediating neurotoxicity of soluble tau forms largely remain to be elucidated, glutamate ionotropic NMDA receptors (NMDARs) have emerged as specific targets of soluble Aβ1–42 (s-Aβ) oligomers. Thanks to its broad positive action on brain cells, FTY720 is emerging as promising neuroprotective agent in a wide range of CNS diseases It exerts therapeutic benefit in preclinical models of stroke[36,37,38] trauma[39], Rett Syndrome[40], epilepsy[41] and AD31,42–44. Multiple mechanisms have been implicated in the protective action of FTY720 in AD, including inhibition of Aβproduction from neurons[42], modulation of microglia activation and cytokine release[30], regulation of the ceramide/S1P balance[46] and up regulation of neuronal brain-derived neurotrophic factor (BDNF)[31,40,43] a key modulator of memory formation[47]. Upregulation of the growth factor may be independent of S1P-R activation, resulting from nuclear action of FTY720, which inhibits histone deacetylases and exerts epigenetic control on genes associated to learning and memory[24], to S1P
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