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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
Author(s) -
Deng Yu,
Wang Zhe,
Wang Ruitao,
Zhang Xiaozhu,
Zhang Shuting,
Wu Yili,
Staufenbiel Matthias,
Cai Fang,
Song Weihong
Publication year - 2013
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.12235
Subject(s) - amyloid precursor protein , amyloid precursor protein secretase , cleavage (geology) , alpha secretase , chemistry , senile plaques , p3 peptide , bace1 as , microbiology and biotechnology , biochemistry , alzheimer's disease , genetically modified mouse , biology , transgene , gene , medicine , paleontology , disease , fracture (geology)
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 ( BACE 1) 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 BACE 1 to generate soluble secreted APP ( sAPP β) 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 sAPP β596 and CTF β 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 BACE 1 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 BACE 1 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 BACE 1 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.