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Amyloid-β protein (Aβ) Glu11 is the major β-secretase site of β-site amyloid-β precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis.
Eur J Neurosci. 2013 Jun; 37(12):1962-9.EJ

Abstract

Cleavage of amyloid-β precursor protein (APP) at the Asp1 β-secretase site of the amyloid-β protein (Aβ) domain by β-site Aβ precursor protein-cleaving enzyme 1 (BACE1) is required for the generation of Aβ, a central component of neuritic plaques in the Alzheimer's disease (AD) brain. In this study, we found that Aβ Glu11 is the major β-secretase site for cleavage of APP by BACE1 to generate soluble secreted APP (sAPPβ)(606) and the C-terminal membrane-bound fragment (CTF)β product C89. Cleavage of C89 by γ-secretase resulted in truncated Aβ generation in a non-amyloidogenic pathway. A familial AD-associated Swedish APP mutation adjacent to Aβ Asp1 shifted the major APP β-secretase cleavage site from Aβ Glu11 to Asp1, resulting in significant increases in sAPPβ596 and CTFβ C99 generation and the C99/89 ratio, in turn leading to increased Aβ production in cultured cells in vitro and transgenic AD model mouse brains in vivo. Furthermore, increased BACE1 expression facilitated APP being processed by the β-secretase processing pathway rather than the α-secretase pathway, leading to more Aβ production. Our results suggest that potentiating BACE1 cleavage of APP at both the Asp1 and Glu11 sites, or shifting the cleavage from the Glu11 site to the Asp1 site, could result in increased Aβ production and facilitate neuritic plaque formation. Our study provides new insights into how alteration of BACE1 expression and β-secretase cleavage site selection could contribute to Alzheimer pathogenesis and the pharmaceutical potential of modulating BACE1 expression and its cleavage site selection.

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Authors+Show Affiliations

Deng Y
Department of Psychiatry, Townsend Family Laboratories, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
Wang Z
No affiliation info available
Wang R
No affiliation info available
Zhang X
No affiliation info available
Zhang S
No affiliation info available
Wu Y
No affiliation info available
Staufenbiel M
No affiliation info available
Cai F
No affiliation info available
Song W
No affiliation info available

MeSH

Alzheimer DiseaseAmyloid Precursor Protein SecretasesAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnimalsAspartic Acid EndopeptidasesCells, CulturedMiceMice, Mutant StrainsMice, Transgenic

Pub Type(s)

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

Language

eng

PubMed ID

23773065

Citation

Deng, Yu, et al. "Amyloid-β Protein (Aβ) Glu11 Is the Major Β-secretase Site of Β-site Amyloid-β Precursor Protein-cleaving Enzyme 1(BACE1), and Shifting the Cleavage Site to Aβ Asp1 Contributes to Alzheimer Pathogenesis." The European Journal of Neuroscience, vol. 37, no. 12, 2013, pp. 1962-9.
Deng Y, Wang Z, Wang R, et al. Amyloid-β protein (Aβ) Glu11 is the major β-secretase site of β-site amyloid-β precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis. Eur J Neurosci. 2013;37(12):1962-9.
Deng, Y., Wang, Z., Wang, R., Zhang, X., Zhang, S., Wu, Y., Staufenbiel, M., Cai, F., & Song, W. (2013). Amyloid-β protein (Aβ) Glu11 is the major β-secretase site of β-site amyloid-β precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis. The European Journal of Neuroscience, 37(12), 1962-9. https://doi.org/10.1111/ejn.12235
Deng Y, et al. Amyloid-β Protein (Aβ) Glu11 Is the Major Β-secretase Site of Β-site Amyloid-β Precursor Protein-cleaving Enzyme 1(BACE1), and Shifting the Cleavage Site to Aβ Asp1 Contributes to Alzheimer Pathogenesis. Eur J Neurosci. 2013;37(12):1962-9. PubMed PMID: 23773065.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amyloid-β protein (Aβ) Glu11 is the major β-secretase site of β-site amyloid-β precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis. AU - Deng,Yu, AU - Wang,Zhe, AU - Wang,Ruitao, AU - Zhang,Xiaozhu, AU - Zhang,Shuting, AU - Wu,Yili, AU - Staufenbiel,Matthias, AU - Cai,Fang, AU - Song,Weihong, PY - 2013/01/09/received PY - 2013/03/07/revised PY - 2013/03/28/accepted PY - 2013/6/19/entrez PY - 2013/6/19/pubmed PY - 2014/1/1/medline SP - 1962 EP - 9 JF - The European journal of neuroscience JO - Eur J Neurosci VL - 37 IS - 12 N2 - Cleavage of amyloid-β precursor protein (APP) at the Asp1 β-secretase site of the amyloid-β protein (Aβ) domain by β-site Aβ precursor protein-cleaving enzyme 1 (BACE1) is required for the generation of Aβ, a central component of neuritic plaques in the Alzheimer's disease (AD) brain. In this study, we found that Aβ Glu11 is the major β-secretase site for cleavage of APP by BACE1 to generate soluble secreted APP (sAPPβ)(606) and the C-terminal membrane-bound fragment (CTF)β product C89. Cleavage of C89 by γ-secretase resulted in truncated Aβ generation in a non-amyloidogenic pathway. A familial AD-associated Swedish APP mutation adjacent to Aβ Asp1 shifted the major APP β-secretase cleavage site from Aβ Glu11 to Asp1, resulting in significant increases in sAPPβ596 and CTFβ C99 generation and the C99/89 ratio, in turn leading to increased Aβ production in cultured cells in vitro and transgenic AD model mouse brains in vivo. Furthermore, increased BACE1 expression facilitated APP being processed by the β-secretase processing pathway rather than the α-secretase pathway, leading to more Aβ production. Our results suggest that potentiating BACE1 cleavage of APP at both the Asp1 and Glu11 sites, or shifting the cleavage from the Glu11 site to the Asp1 site, could result in increased Aβ production and facilitate neuritic plaque formation. Our study provides new insights into how alteration of BACE1 expression and β-secretase cleavage site selection could contribute to Alzheimer pathogenesis and the pharmaceutical potential of modulating BACE1 expression and its cleavage site selection. SN - 1460-9568 UR - https://www.unboundmedicine.com/medline/citation/23773065/Amyloid_β_protein__Aβ__Glu11_is_the_major_β_secretase_site_of_β_site_amyloid_β_precursor_protein_cleaving_enzyme_1_BACE1__and_shifting_the_cleavage_site_to_Aβ_Asp1_contributes_to_Alzheimer_pathogenesis_ L2 - https://doi.org/10.1111/ejn.12235 DB - PRIME DP - Unbound Medicine ER -