On the possible structural role of single chain sphingolipids Sphingosine and Sphingosine 1-phosphate in the amyloid-β peptide interactions with membranes. Consequences for Alzheimer’s disease development

Abstract

A strong interplay between the neurodegerative effects of the amyloid β (Aβ) peptides and the cell lipid composition or metabolism has been evidenced in Alzheimer’s disease. This appears to be, in part, related to Aβ-membrane interactions. Recently, an influence of the two cell fate-modulating single-chain sphingolipids, sphingosine (Sph) and sphingosine 1-phosphate (S1P), on AD-related mechanisms has been reported. We have investigated the influence of Sph and S1P on the interaction of Aβ(1–42) with lipid model membranes. A fluorescent Aβ(1–42) binds to egg phosphatidylcholine (EPC) giant unilamellar vesicles containing Sph or S1P. With Sph, gel microdomains are present at low temperature and Aβ(1–42) binds preferentially to these domains, especially at their boundaries. With S1P, which displays single lipid phase morphology, Aβ(1–42) binding is uniform. The binding of Aβ(1–42) to EPC/sphingolipid large unilamellar vesicles was investigated by spectrofluorimetry using the 2 probes Laurdan and di-ANEPPS. With most lipid compositions the binding of Aβ(1–42) to LUVs appears superficial. However, with Sph, a deeper membrane penetration is observed. This deeper interaction is reversed to superficial by the simultaneous presence of S1P. It is suggested that the influence of single-chain sphingolipids in AD might be related to a selective interaction of Aβ(1–42) with sphingosine in membranes, that is antagonized by S1P. Such interaction might occur intracellularly for Aβ(1–42) monomers or oligomers and/or extracellularly for Aβ still part of APP. Aβ(1–42) might also influence microdomains by binding to their boundaries. The influence of the Sph/S1P balance on the Alzheimer pathology might be related in part to the differential interactions of Aβ(1–42) with Sph and S1P and their effects on membrane domains.