title: Presenilin 1 is involved in the maturation of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1).
abstract: One of the pathologic hallmarks of Alzheimer's disease is the excessive deposition of beta-amyloid peptides (Abeta) in senile plaques. Abeta 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 Abeta 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 beta- and gamma-secretase in Abeta generation.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kuzuya
authors.forename: Kengo
authors.initials: K
authors.lastname: Uemura
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kitagawa
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Aoyagi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kihara
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology; D037281:Calnexin / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008361:Mannosidases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1 / Q000172:deficiency / Q000502:physiology*; D053766:Presenilin-2 / Q000172:deficiency; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013912:Threonine / Q000235:genetics; D014162:Transfection / Q000379:methods
chemical_list: D053764:Presenilin-1; D053766:Presenilin-2; D012333:RNA, Messenger; D037281:Calnexin; D013912:Threonine; D001224:Aspartic Acid; D008361:Mannosidases; C038829:mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse