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 disease (AD). Prefibrillar oligomers of the 42‐residue form of Aβ (Aβ 42 O) show membrane‐binding capacity and trigger the disruption of Ca 2+ homeostasis, a causative event in neuron degeneration. Since bioactive lipids have been recently proposed as potent protective agents against Aβ toxicity, we investigated the involvement of sphingosine 1‐phosphate (S1P) signalling pathway in Ca 2+ homeostasis in living neurons exposed to Aβ 42 O. We show that both exogenous and endogenous S1P rescued neuronal Ca 2+ dyshomeostasis induced by toxic Aβ 42 O in primary rat cortical neurons and human neuroblastoma SH‐SY5Y cells. Further analysis revealed a strong neuroprotective effect of S1P 1 and S1P 4 receptors, and to a lower extent of S1P 3 and S1P 5 receptors, which activate the G i ‐dependent signalling pathways, thus resulting in the endocytic internalization of the extrasynaptic GluN2B‐containing N ‐methyl‐ D ‐aspartate receptors (NMDARs). Notably, the S1P beneficial effect can be sustained over time by sphingosine kinase‐1 overexpression, thus counteracting the down‐regulation of the S1P signalling induced by Aβ 42 O. Our findings disclose underlying mechanisms of S1P neuronal protection against harmful Aβ 42 O, suggesting that S1P and its signalling axis can be considered promising targets for therapeutic approaches for AD.