Issue 7, 2021

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

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-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, that SP is capable of interacting with both Aβ and metal ions and consequently affects the aggregation of metal-free Aβ and metal–Aβ. Moreover, incubation of SP with 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 of SP, N-acetylsphingosine and 3-O-acetylsphingosine also influence metal-free Aβ and metal–Aβ aggregation to different degrees, compared to SP. Such slight structural modifications of SP neutralize its ability to exacerbate the cytotoxicity triggered by metal-free Aβ and metal–Aβ. Notably, the reactivity of SP and 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 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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
10 8 2020
Accepted
16 12 2020
First published
17 12 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 2456-2466

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

Y. Yi, Y. Lin, J. Han, H. J. Lee, N. Park, G. Nam, Y. S. Park, Y. Lee and M. H. Lim, Chem. Sci., 2021, 12, 2456 DOI: 10.1039/D0SC04366D

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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