Lipid rafts and their component, cholesterol, modulate the processing of β-amyloid precursor protein (APP). However, the role of sphingolipids, another major component of lipid rafts, in APP processing remains undetermined. Here we report the effect of sphingolipid deficiency on APP processing in Chinese hamster ovary cells treated with a specific inhibitor of serine palmitoyltransferase, which catalyzes the first step of sphingolipid biosynthesis, and in a mutant LY-B strain defective in the LCB1 subunit of serine palmitoyltransferase. We found that in sphingolipid-deficient cells, the secretion of soluble APPα (sAPPα) and the generation of C-terminal fragment cleaved at α-site dramatically increased, whereas β-cleavage activity remained unchanged, and the ε-cleavage activity decreased without alteration of the total APP level. The secretion of amyloid β-protein 42 increased in sphingolipid-deficient cells, whereas that of amyloid β-protein 40 did not. All of these alterations were restored in sphingolipid-deficient cells by adding exogenous sphingosine and in LY-B cells by transfection with cLCB1. Sphingolipid deficiency increased MAPK/ERK activity and a specific inhibitor of MAPK kinase, PD98059, restored sAPPα level, indicating that sphingolipid deficiency enhances sAPPα secretion via activation of MAPK/ERK pathway. These results suggest that not only the cellular level of cholesterol but also that of sphingolipids may be involved in the pathological process of Alzheimer's disease by modulating APP cleavage.
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