Liu Kangning, Doms Robert W, Lee Virginia M-Y
The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Biochemistry. 2002 Mar 5;41(9):3128-36. doi: 10.1021/bi015800g.
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.
淀粉样β肽（Aβ）由淀粉样β前体蛋白（APP）的蛋白水解加工产生。新发现的β位点APP裂解酶（BACE）在天冬氨酸1处以及Aβ的酪氨酸10和谷氨酸11之间裂解APP，分别产生C末端片段（CTF）C99和C89。随后γ-分泌酶的裂解产生Aβ1-40/42和Aβ11-40/42。尽管在AD大脑的淀粉样斑块中已鉴定出全长和在残基11处截短的Aβ肽，但BACE产生并由培养细胞分泌到培养基中的这两种裂解产物的相对比例尚不清楚。使用稳定过表达BACE的细胞系，我们发现Aβ11-40和Aβ11-42是BACE产生的主要Aβ裂解产物。我们进一步表明，BACE利用全长APP以及C99作为产生C89的底物，并且Aβ11-40/42可以通过BACE和γ-分泌酶对单个APP分子的顺序裂解产生。综上所述，BACE产生的Aβ11-40/42的丰度表明它们在AD发病机制中的作用可能被低估了。
