Alzheimer's β-Secretase, β-Site Amyloid Precursor Protein-Cleaving Enzyme, is Responsible for Cleavage Secretion of a Golgi-Resident Sialyltransferase

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 24; pp. 13554 - 13559
• Main Authors: Kitazume, Shinobu, Tachida, Yuriko, Oka, Ritsuko, Shirotani, Keiro, Saido, Takaomi C., Hashimoto, Yasuhiro
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.11.2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Alzheimer Disease; Alzheimer's disease; Alzheimers disease; Amino Acid Sequence; Amino acids; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases; Amyloids; Animals; Antibodies; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; beta-D-Galactoside alpha 2-6-Sialyltransferase; Biological Sciences; Brain; Cell Line; Chlorocebus aethiops; Complementary DNA; COS Cells; Endopeptidases; Enzymes; Golgi Apparatus - metabolism; HEK293 cells; Humans; Molecular Sequence Data; Mutagenesis; Peptides; Proteins; Radioactive decay; Secretion; sialyltransferase; Sialyltransferases - genetics; Sialyltransferases - metabolism; Substrate Specificity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.241509198

The deposition of amyloid β-peptide (Aβ) in the brain is closely associated with the development of Alzheimer's disease. Aβ is generated from the amyloid precursor protein (APP) by sequential action of β-secretase (BACE1) and γ-secretase. Although BACE1 is distributed among various other tissues, its physiological substrates other than APP have yet to be identified. ST6Gal I is a sialyltransferase that produces a sialylα2,6galactose residue, and the enzyme is secreted out of the cell after proteolytic cleavage. We report here that BACE1 is involved in the proteolytic cleavage of ST6Gal I, on the basis of the following observations. ST6Gal I was colocalized with BACE1 in the Golgi apparatus by immunofluorescence microscopy, suggesting that BACE1 acts on ST6Gal I within the same intracellular compartment. When BACE1 was overexpressed with ST6Gal I in COS cells, the secretion of ST6Gal I markedly increased. When APPSW(Swedish familial Alzheimer's disease mutation), a preferable substrate for BACE1, was coexpressed with ST6Gal I in COS cells, the secretion of ST6Gal I significantly decreased, suggesting that that the β-cleavage of overexpressed APPSWcompetes with ST6Gal I processing. In addition, BACE1-Fc (Fc, the hinge and constant region of IgG) chimera cleaved protein A-ST6Gal I fusion protein in vitro. Thus, we conclude that BACE1 is responsible for the cleavage and secretion of ST6Gal I.