In vivo cleavage of alpha2,6-sialyltransferase by Alzheimer beta-secretase.
beta-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a membrane-bound aspartic protease that cleaves amyloid precursor protein to produce a neurotoxic peptide, Abeta, and is implicated in triggering the pathogenesis of Alzheimer disease. We previously reported that BACE1 cleaved rat beta-galactoside alpha2,6-sialyltransferase (ST6Gal I) that was overexpressed in COS cells and that the NH(2) terminus of ST6Gal I secreted from the cells (E41 form) was Glu(41). Here we report that BACE1 gene knock-out mice have one third as much plasma ST6Gal I as control mice, indicating that BACE1 is a major protease which is responsible for cleaving ST6Gal I in vivo. We also found that BACE1-transgenic mice have increased level of ST6Gal I in plasma. Secretion of ST6Gal I from the liver into the plasma is known to be up-regulated during the acute-phase response. To investigate the role of BACE1 in ST6Gal I secretion in vivo, we analyzed the levels of BACE1 mRNA in the liver, as well as the plasma levels of ST6Gal I, in a hepatopathological model, i.e. Long-Evans Cinnamon (LEC) rats. This rat is a mutant that spontaneously accumulates copper in the liver and incurs hepatic damage. LEC rats exhibited simultaneous increases in BACE1 mRNA in the liver and in the E41 form of the ST6Gal I protein, the BACE1 product, in plasma as early as 6 weeks of age, again suggesting that BACE1 cleaves ST6Gal I in vivo and controls the secretion of the E41 form.
Kitazume
Shinobu
S
Glyco-chain Functions Laboratory, The Institute of Physical and Chemical Research, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Nakagawa
Kazuhiro
K
Oka
Ritsuko
R
Tachida
Yuriko
Y
Ogawa
Kazuko
K
Luo
Yi
Y
Citron
Martin
M
Shitara
Hiroshi
H
Taya
Choji
C
Yonekawa
Hiromichi
H
Paulson
James C
JC
Miyoshi
Eiji
E
Taniguchi
Naoyuki
N
Hashimoto
Yasuhiro
Y
D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology; D010450:Endopeptidases / Q000378:metabolism* / Q000502:physiology*; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism; D047468:Immunoprecipitation; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012799:Sialyltransferases / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D020033:Protein Isoforms; D012333:RNA, Messenger; D012799:Sialyltransferases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase