FTY720/Fingolimod, a Sphingosine Analogue, Reduces Amyloid-β Production in Neurons

Abstract

Sphingosine-1-phosphate (S1P) is a pluripotent lipophilic mediator working as a ligand for G-protein coupled S1P receptors (S1PR), which is currently highlighted as a therapeutic target for autoimmune diseases including relapsing forms of multiple sclerosis. Sphingosine related compounds, FTY720 and KRP203 known as S1PR modulators, are phosphorylated by sphingosine kinase 2 (SphK2) to yield the active metabolites FTY720-P and KRP203-P, which work as functional antagonists for S1PRs. Here we report that FTY720 and KRP203 decreased production of Amyloid-β peptide (Aβ), a pathogenic proteins causative for Alzheimer disease (AD), in cultured neuronal cells. Pharmacological analyses suggested that the mechanism of FTY720-mediated Aβ decrease in cells was independent of known downstream signaling pathways of S1PRs. Unexpectedly, 6-days treatment of APP transgenic mice with FTY720 resulted in a decrease in Aβ40, but an increase in Aβ42 levels in brains. These results suggest that S1PR modulators are novel type of regulators for Aβ metabolisms that are active in vitro and in vivo.

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

“…This phenomenon is exploited in its therapeutic applications thus far, but makes interpretation of the results of its experimental administration much more difficult. Chronic, peripheral FTY720 treatment has been shown to attenuate histological damage and reduce behavioral deficits in the hippocampal CA1 field of Aβ 42 -injected rats [64]; in vitro FTY720 is able to reduce Aβ production by primary mouse neurons, although with some increase of the Aβ 42 /Aβ 40 ratio [65]. The mechanism of fingolimod's action may include effects on apoptotic signaling (as an S1P analog, it may counteract the effects of ceramide), or on AβPP/Aβ metabolism.…”

Sphingosine-1-Phosphate: Boon and Bane for the Brain

“…Concordantly, FTY720 reduced Aβ release in cultured neurons, apparently independent of known downstream signaling pathways of S1PRs [74]. FTY720 was also found to attenuate Aβ-induced cognitive impairment and neuronal damage in the hippocampus of rats [75].…”

Original article Sphingosine kinases modulate the secretion of amyloid β precursor protein from SH-SY5Y neuroblastoma cells: the role of α-synuclein

“…Each may be an important factor of AD albeit in different ways. Sphingolipid signalling may influence Aβ production [29,32,34] and siRNA/inhi bition of SphK1/SphK2 reduces βcleavage of APP leading to lower the secretion of Aβ and sAPPβ [33]. SphKs and sphingolipids may also modulate Aβ tox icity [7,10] and the inflammation it causes [18] as well as the resulting brain tissue damage [2].…”