Sulfatides facilitate apolipoprotein E-mediated amyloid-beta peptide clearance through an endocytotic pathway.
Amyloid-beta (Abeta) accumulation and fibril formation are key pathologic characteristics of Alzheimer's disease (AD). We have previously found that sulfatide depletion occurs at the earliest stages of AD. To further identify the role of sulfatides in the pathogenesis of AD as well as the interactions between apolipoprotein E (apoE), sulfatides, and Abeta peptides, we examined alterations in the clearance of apoE-mediated Abeta peptides after sulfatide supplementation to cell culture systems. We demonstrated that sulfatides markedly facilitate apoE-mediated clearance of Abeta peptides endogenously generated from H4-APPwt cells through an endocytotic pathway. Moreover, we found that the uptake of Abeta42 mediated by sulfatides was selective in comparison to that of Abeta40. We excluded the possibility that the supplementation of sulfatides and/or apoE altered the production of Abeta peptides from H4-APPwt cells through determination of the clearance of Abeta peptides from conditioned H4-APPwt cell media by neuroblastoma cells which do not appreciably generate Abeta peptides. Finally, we demonstrated that the sulfate galactose moiety of sulfatides is essential for the sulfatide-facilitated clearance of Abeta peptides. Collectively, the current study provides insight into a molecular mechanism leading to Abeta clearance/deposition, highlights the significance of sulfatide deficiency at the earliest clinically recognizable stage of AD, and identifies a potential new direction for therapeutic intervention for the disease.
Zeng
Youchun
Y
Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Han
Xianlin
X
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D002417:Cattle; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004705:Endocytosis / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013433:Sulfoglycosphingolipids / Q000494:pharmacology*; D022161:Transport Vesicles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; D013433:Sulfoglycosphingolipids; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)