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Presenilin 1 is involved in the maturation of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1).
J Neurosci Res. 2007 Jan; 85(1):153-65.JN

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+Show Affiliations

Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17075903

Citation

Kuzuya, Akira, et al. "Presenilin 1 Is Involved in the Maturation of Beta-site Amyloid Precursor Protein-cleaving Enzyme 1 (BACE1)." Journal of Neuroscience Research, vol. 85, no. 1, 2007, pp. 153-65.
Kuzuya A, Uemura K, Kitagawa N, et al. Presenilin 1 is involved in the maturation of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). J Neurosci Res. 2007;85(1):153-65.
Kuzuya, A., Uemura, K., Kitagawa, N., Aoyagi, N., Kihara, T., Ninomiya, H., Ishiura, S., Takahashi, R., & Shimohama, S. (2007). Presenilin 1 is involved in the maturation of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). Journal of Neuroscience Research, 85(1), 153-65.
Kuzuya A, et al. Presenilin 1 Is Involved in the Maturation of Beta-site Amyloid Precursor Protein-cleaving Enzyme 1 (BACE1). J Neurosci Res. 2007;85(1):153-65. PubMed PMID: 17075903.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Presenilin 1 is involved in the maturation of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). AU - Kuzuya,Akira, AU - Uemura,Kengo, AU - Kitagawa,Naoyuki, AU - Aoyagi,Nobuhisa, AU - Kihara,Takeshi, AU - Ninomiya,Haruaki, AU - Ishiura,Shoichi, AU - Takahashi,Ryosuke, AU - Shimohama,Shun, PY - 2006/11/1/pubmed PY - 2007/3/22/medline PY - 2006/11/1/entrez SP - 153 EP - 65 JF - Journal of neuroscience research JO - J. Neurosci. Res. VL - 85 IS - 1 N2 - 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. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/17075903/Presenilin_1_is_involved_in_the_maturation_of_beta_site_amyloid_precursor_protein_cleaving_enzyme_1__BACE1__ L2 - https://doi.org/10.1002/jnr.21104 DB - PRIME DP - Unbound Medicine ER -