The Contribution of Cholesterol and Sphingolipids in APP Processing

The cholesterol content of lipid rafts has been shown to contribute to the integrity of raft structure and the function of lipid rafts in signaling and membrane trafficking [4,135]. In addition, the results of several studies have shown that sphingolipids modulate raft functions [136,137].

A very recent report [138] examined the changes in APP processing and Ab generation in sphingolipid-deficient cells, thus demonstrating the importance of sphingolipid levels for modulating APP processing. In particular, it has been shown that sphingolipid deficiency enhances sAPPa secretion via activation of the MAPK/ERK pathway, though the mechanism by which sphingolipid deficiency enhances ERK activity is as yet unknown. Interestingly, cholesterol depletion is reported to increase sAPPa secretion rates, although it is not known whether the MAPK/ERK pathway is involved in this cholesterol depletion-mediated pathway [83].

Furthermore, the possibility that cholesterol and sphingolipids depletion enhances APP a-cleavage in different ways cannot be excluded. Previous reports have shown that cholesterol depletion causes a decrease in b-cleavage activity and an increase in a-cleavage activity of APP [102]. In contrast, under conditions in which cholesterol levels are unchanged and lipid raft dysfunction is caused by sphingo-lipid depletion, the a-cleavage of APP is enhanced without affecting the b-cleavage activity of APP or the APP level in lipid rafts. These findings could suggest that sphingolipid depletion may enhance a-cleavage of APP without shifting the intracellular trafficking of APP from the "Ab generation site" (lipid rafts) to the "Ab nongeneration site" (outside rafts).

Therefore, cholesterol and sphingolipids may play different roles in affecting a-and b-cleavage of APP. Interestingly, also in the case of prion diseases, the effect of sphingolipid depletion on the formation of scrapie prion protein is opposite to that of cholesterol depletion [33,76].

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