Presenilin 1 is involved in the maturation of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1)
Presenilin 1 is involved in the maturation of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1)
复制标题
DOI：
10.1002/jnr.21104
复制
发表时间：
2007-01-01
影响因子：
4.2
通讯作者：
Shimohama, Shun
中科院分区：
文献类型：
--
作者：
Kuzuya, Akira;Uemura, Kengo;Shimohama, Shun
阿尔茨海默病的病理学特征之一是β-淀粉样肽（A β）在老年斑中的过度沉积。当β-淀粉样前体蛋白（APP）依次被β-分泌酶（鉴定为β-位点APP裂解酶1（BACE 1））和γ-分泌酶（一种推定的含有早老素1（PS1）的酶复合物）裂解时，产生β。然而，PS1和BACE 1之间的功能相互作用从未被发现。除了在产生A β肽中的这种经典作用之外，还提出PS1影响选定膜蛋白的细胞内运输和成熟。我们发现，早老素缺陷小鼠胚胎成纤维细胞（PS-/-MEFs）中表达的外源性和内源性成熟BACE 1的水平显着降低相比，野生型MEFs。此外，与天然细胞相比，在稳定表达野生型PS1的人神经母细胞瘤细胞系SH-SY 5 Y中成熟BACE 1的水平增加。相反，BACE 1的成熟在显性负突变PS1过表达的稳定表达下受到损害。免疫沉淀实验表明，PSI优先与proBACE 1而不是成熟BACE 1相互作用，表明PS1可直接参与BACE 1的成熟过程。此外，内源性PS1与内源性BACE 1在SH-SY 5 Y细胞和小鼠脑组织中免疫沉淀。我们的结论是，PS1是直接参与BACE 1的成熟，因此可能作为一个调节器的β-和γ-分泌酶在A β代。(c)2006 Wiley-Liss，Inc.
One of the pathologic hallmarks of Alzheimer's disease is the excessive deposition of beta-amyloid peptides (A beta) in senile plaques. A beta is generated when beta-amyloid precursor protein (APP) is cleaved sequentially by beta-secretase, identified as beta-site APP-cleaving enzyme 1 (BACE1), and, gamma-secretase, a putative enzymatic complex containing presenilin 1 (PS1). However, functional interaction between PS1 and BACE1 has never been known. In addition to this classical role in the generation of A beta peptides, it has also been proposed that PS1 affects the intracellular trafficking and maturation of selected membrane proteins. We show that the levels of exogenous and endogenous mature BACE1 expressed in presenilin-deficient mouse embryonic fibroblasts (PS-/-MEFs) were reduced significantly compared to those in wild-type MEFs. Moreover, the levels of mature BACE1 were increased in human neuroblastoma cell line, SH-SY5Y, stably expressing wildtype PS1, compared to native cells. Conversely, the maturation of BACE1 was compromised under the stable expression of dominant-negative mutant PS1 overexpression. Immunoprecipitation assay showed that PSI preferably interacts with proBACE1 rather than mature BACE1, indicating that PS1 can be directly involved in the maturation process of BACE1. Further, endogenous PS1 was immunoprecipitated with endogenous BACE1 in SH-SY5Y cells and mouse brain tissue. We conclude that PS1 is directly involved in the maturation of BACE1, thus possibly functioning as a regulator of both beta- and gamma-secretase in A beta generation. (c) 2006 Wiley-Liss, Inc.