Presenilin 1 is involved in the maturation of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1)

✍ Scribed by Akira Kuzuya; Kengo Uemura; Naoyuki Kitagawa; Nobuhisa Aoyagi; Takeshi Kihara; Haruaki Ninomiya; Shoichi Ishiura; Ryosuke Takahashi; Shun Shimohama

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 927 KB
• Volume: 85
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.21104

✦ Synopsis

Abstract

One of the pathologic hallmarks of Alzheimer's disease is the excessive deposition of β‐amyloid peptides (Aβ) in senile plaques. Aβ is generated when β‐amyloid precursor protein (APP) is cleaved sequentially by β‐secretase, identified as β‐site APP‐cleaving enzyme 1 (BACE1), and γ‐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 Aβ 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 wild‐type 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 PS1 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 β‐ and γ‐secretase in Aβ generation. © 2006 Wiley‐Liss, Inc.