Glu11 site cleavage and N-terminally truncated A beta production upon BACE overexpression.
Amyloid beta peptides (A beta) are generated by the proteolytic processing of the amyloid beta precursor protein (APP). The newly identified beta-site APP-cleaving enzyme (BACE) cleaves APP at Asp1 as well as between Tyr10 and Glu11 of A beta, producing C-terminal fragments (CTFs) C99 and C89, respectively. Subsequent cleavage by gamma-secretase gives rise to A beta 1-40/42 and A beta 11-40/42. Although both full-length and A beta peptides truncated at residue 11 have been identified in amyloid plaques in the AD brain, the relative proportion of these two cleavage products produced by BACE and secreted into the medium by cultured cells is unknown. Using cell lines stably overexpressing BACE, we found that A beta 11-40 and A beta 11-42 are major A beta cleavage products generated by BACE. We further showed that BACE utilizes both full-length APP as well as C99 as substrates for the production of C89, and that A beta 11-40/42 can be generated by sequential cleavage of single APP molecules by BACE and gamma-secretase. Taken together, the abundance of A beta 11-40/42 produced by BACE suggests that their roles in AD pathogenesis may be underestimated.
Liu
Kangning
K
The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Doms
Robert W
RW
Lee
Virginia M-Y
VM
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001224:Aspartic Acid / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D010450:Endopeptidases; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C092862:amyloid beta-protein (10-43); D001224:Aspartic Acid; D018698:Glutamic Acid; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human