Impact of sphingosine and acetylsphingosines on the aggregation and toxicity of metal-free and metal-treated amyloid-β

Pathophysiological shifts in the cerebral levels of sphingolipids in Alzheimer's disease (AD) patients suggest a link between sphingolipid metabolism and the disease pathology. Sphingosine (SP), a structural backbone of sphingolipids, is an amphiphilic molecule that is able to undergo aggregation into micelles and micellar aggregates. Considering its structural properties and cellular localization, we hypothesized thatSPpotentially interacts with amyloid-β (Aβ) and metal ions that are found as pathological components in AD-affected brains, with manifesting its reactivity towards metal-free Aβ and metal-bound Aβ (metal-Aβ). Herein, we report,for the first time, thatSPis capable of interacting with both Aβ and metal ions and consequently affects the aggregation of metal-free Aβ and metal-Aβ. Moreover, incubation ofSPwith Aβ in the absence and presence of metal ions results in the aggravation of toxicity induced by metal-free Aβ and metal-Aβ in living cells. As the simplest acyl derivatives ofSP,N-acetylsphingosine and 3-O-acetylsphingosine also influence metal-free Aβ and metal-Aβ aggregation to different degrees, compared toSP. Such slight structural modifications ofSPneutralize its ability to exacerbate the cytotoxicity triggered by metal-free Aβ and metal-Aβ. Notably, the reactivity ofSPand the acetylsphingosines towards metal-free Aβ and metal-Aβ is determined to be dependent on their formation of micelles and micellar aggregates. Our overall studies demonstrate thatSPand its derivatives could directly interact with pathological factors in AD and modify their pathogenic properties at concentrations below and above critical aggregation concentrations.