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

Abstract

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 that SP potentially interacts with amyloid-beta (A beta) and metal ions that are found as pathological components in AD-affected brains, with manifesting its reactivity towards metal-free A beta and metal-bound A beta (metal-A beta). Herein, we report, for the first time, that SP is capable of interacting with both A beta and metal ions and consequently affects the aggregation of metal-free A beta and metal-A beta. Moreover, incubation of SP with A beta in the absence and presence of metal ions results in the aggravation of toxicity induced by metal-free A beta and metal-A beta in living cells. As the simplest acyl derivatives of SP, N-acetylsphingosine and 3-O-acetylsphingosine also influence metal-free A beta and metal-A beta aggregation to different degrees, compared to SP. Such slight structural modifications of SP neutralize its ability to exacerbate the cytotoxicity triggered by metal-free A beta and metal-A beta. Notably, the reactivity of SP and the acetylsphingosines towards metal-free A beta and metal-A beta is determined to be dependent on their formation of micelles and micellar aggregates. Our overall studies demonstrate that SP and its derivatives could directly interact with pathological factors in AD and modify their pathogenic properties at concentrations below and above critical aggregation concentrations.