A bidirectional link between sulfatide and Alzheimers disease

Published: 17 November 2023| Version 1 | DOI: 10.17632/f8m4kd26sm.1
Marcus Grimm, Valerie Zimmer


Reduced sulfatide-level are found in Alzheimer’s disease (AD) patients. Here we demonstrate that amyloid-precursor-protein (APP) processing regulates sulfatide-synthesis and vice versa. Differentcell culture model 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 Abeta-generation by reducing beta-secretase- (BACE1) and gamma-secretase-processing of APP. Increased BACE1 lysosomal-degradation lead to reduced BACE1-protein level in endosomes. Reduced gamma-secretase-activity is caused by a direct effect on gamma-secretase-activity and reduced amounts ofgamma-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 gamma-secretase-activity. Human brain APP level shows a significant negative correlation with GAL3STal3st1/CST-expression underlining the in vivo relevance of sulfatide-homeostasis in AD. The here shown data represents the images from the atomic force microscopy to detect Abeta-fibrils in the presence or absence of sulfates. Moreover, an excel-sheet containing the 1-letter codes of the synthetic peptides used in this study is given.