A bidirectional link between sulfatide and Alzheimer's disease.

Reduced sulfatide level is found in Alzheimer's disease (AD) patients. Here, we demonstrate that amyloid precursor protein (APP) processing regulates sulfatide synthesis and vice versa. Different cell culture models and transgenic mice models devoid of APP processing or in particular the APP intracellular domain (AICD) reveal that AICD decreases Gal3st1/CST expression and subsequently sulfatide synthesis. In return, sulfatide supplementation decreases Aβ generation by reducing β-secretase (BACE1) and γ-secretase processing of APP. Increased BACE1 lysosomal degradation leads to reduced BACE1 protein level in endosomes. Reduced γ-secretase activity is caused by a direct effect on γ-secretase activity and reduced amounts of γ-secretase components in lipid rafts. Similar changes were observed by analyzing cells and mice brain samples deficient of arylsulfatase A responsible for sulfatide degradation or knocked down in Gal3st1/CST. In line with these findings, addition of sulfatides to brain homogenates of AD patients resulted in reduced γ-secretase activity. Human brain APP level shows a significant negative correlation with GAL3ST1/CST expression underlining the in vivo relevance of sulfatide homeostasis in AD. [Display omitted] • Sulfatide levels are reduced in human brain of Alzheimer's disease patients • AICD inhibits CST gene expression and thereby reduces sulfatide synthesis • In return, sulfatide decreases amyloidogenic processing and Aβ production • Aβ aggregation is inhibited in presence of sulfatide compared to ceramide Zimmer et al. report that the glycosphingolipid sulfatide is reduced in brains of Alzheimer's patients. AICD inhibits CST expression, necessary for sulfatide synthesis. In return, sulfatides inhibit amyloidogenic APP processing by enhancing lysosomal BACE1 degradation and reducing γ-secretase activity due to shift from raft to non-raft fraction resulting in a bidirectional link between APP processing and sulfatides. [ABSTRACT FROM AUTHOR]