Sphingosine 1-phosphate attenuates neuronal dysfunction induced by amyloid-β oligomers through endocytic internalization of NMDA receptors

Soluble oligomers arising from the aggregation of the amyloid beta peptide(Aβ) have been identified as the main pathogenic agents in Alzheimer’s dis-ease (AD). Prefibrillar oligomers of the 42-residue form of Aβ(Aβ42O)show membrane-binding capacity and trigger the disruption of Ca2+home-ostasis, a causative event in neuron degeneration. Since bioactive lipidshave been recently proposed as potent protective agents against Aβtoxic-ity, we investigated the involvement of sphingosine 1-phosphate (S1P) sig-nalling pathway in Ca2+homeostasis in living neurons exposed to Aβ42O.We show that both exogenous and endogenous S1P rescued neuronal Ca2+dyshomeostasis induced by toxic Aβ42O in primary rat cortical neuronsand human neuroblastoma SH-SY5Y cells. Further analysis revealed astrong neuroprotective effect of S1P1and S1P4receptors, and to a lowerextent of S1P3and S1P5receptors, which activate the Gi-dependent sig-nalling pathways, thus resulting in the endocytic internalization of theextrasynaptic GluN2B-containingN-methyl-D-aspartate receptors(NMDARs). Notably, the S1P beneficial effect can be sustained over timeby sphingosine kinase-1 overexpression, thus counteracting the down-regulation of the S1P signalling induced by Aβ42O. Our findings discloseunderlying mechanisms of S1P neuronal protection against harmful Aβ42O,suggesting that S1P and its signalling axis can be considered promising tar-gets for therapeutic approaches for AD.