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

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.

The Anti-Diabetic Drug Metformin Reduces BACE1 Protein Level by Interfering with the MID1 Complex

“…The disease was first described in 1906 by Alois Alzheimer [1], [2], who observed two pathological hallmarks in patients’ brains: senile plaques, which consist of Aβ peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Aβ peptides are formed by sequential proteolytic cleavage of the amyloid precursor protein (APP).…”

“…BACE1 can cleave APP at two different sites: at Aβ Asp1, producing Aβ in the amyloidogenic pathway; or Aβ Glu11, producing truncated non-amyloidogenic Aβ. Under physiological conditions, BACE1 cleaves APP at Glu11, whereas cleavage at the Asp1-site is enhanced in AD models [2]. BACE1 has a paralogue, BACE2, that shares 64% amino acid similarity.…”

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

“…The mutation may well be reducing the cellular dysfunction that can accompany an over-vigorous protective response, much as reducing inflammatory responses can reduce cancer risk [160] or improve wound healing [161]. This is supported by the work of Weihong Song and colleagues [162] who showed that, in fact, the most common site of cleavage of A␤PP by BACE1 is the ␤' site that prevents A␤ formation by forming a shorter peptide (see Fig. 1).…”

Glucose-6-phosphate dehydrogenase deficiency and Alzheimer’s disease: Partners in crime? The hypothesis

“…For these reasons, b-secretase and APP-cleaving enzymes have preventive and therapeutic properties in this life-threatening disease [35,36]. One of the novel findings on AD is that, APP is processed by a-secretase, b-secretase, theta-secretase, and c-secretase enzymes and the non-amyloidogenic Glu11 site being the major b-secretase cleavage site of BACE1 [37]. It has been established that c-secretase inhibitors lead to accumulation of amyloid precursor [38].…”