Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence

Abstract

Edited by F. Anne Stephenson␤␤-Site APP-cleaving enzyme 1 (BACE1), 3 a type I transmembrane aspartic protease, was identified as the ␤-secretase that cleaves amyloid ␤-protein precursor (APP) to generate neurotoxic amyloid ␤ (A␤) (1-4). BACE1 cleaves APP at the peptide bond between Met 671 and Asp 672 (␤-site; sequence numbering refers to the APP770 isoform) (5, 6). This primary cleavage of APP generates the secreted form of the amino-terminal large fragment (sAPP␤) and the membrane-associated carboxyl-terminal fragment (CTF␤/C99) (reviewed in Ref. 7). Because CTF␤/C99 includes the complete amino acid sequence of the A␤ region, and subsequent cleavage of CTF␤/C99 by ␥-secretase generates the A␤(1-XX) peptides (A␤1 indicates the position of Asp 672 ), the ␤-site cleavage is referred to as amyloidogenic processing of APP (reviewed in Ref. 8). Alternatively, APP can also be cleaved by ␣-secretase (mainly ADAM10/17), at the peptide bond between Lys 687 and Leu 688 , generating sAPP␣ and CTF␣/C83 including the A␤(17-XX) region; accordingly, this cleavage is referred to as amyloidolytic processing of APP (9 -11). BACE1 also cleaves APP at another peptide bond between Tyr 681 and Gln 682 (␤Ј-site), resulting in generation of sAPP␤Ј and CTF␤Ј/C89 (12, 13). Cleavage of CTF␤Ј/C89 by ␥-secretase yields A␤(11-XX), which lacks the first 10 amino acids of the A␤ domain. This ␤Ј-site cleavage of APP is also thought to be amyloidolytic, because the structural analysis suggests that A␤(11-40) and A␤(11-42) are less toxic than A␤(1-40) and A␤(1-42) (14), and the A␤(11-42) showed reduced neurotoxicity compared with A␤(1-42) and A␤(3-42) in a study with transgenic fly (15), although the neurotoxicity of A␤(11-XX) in human brain is controversial (16).A␤ is the major protein component of senile plaques observed in the brain of Alzheimer's disease (AD) subjects, and soluble A␤ oligomer(s) are thought to impair synaptic functions prior to A␤ deposition in the brain (17)(18)(19). Therefore, to understand AD pathogenesis and develop effective AD ther-

The trans-Golgi network is a major site for α-secretase processing of amyloid precursor protein in primary neurons

“…sAPP␣ in the conditioned medium is recognized by the W0-2 antibody, whereas sAPP␤ is not detected by antibody W0-2 as it lacks the epitope. However, an alternative minor BACE1 cleavage site of APP, the ␤Ј-site at residue 10 within the A␤ domain (45), would result in the release of the product sAPP␤Ј and would be recognized by the W0-2 antibody. We demonstrated that most if not all the secreted 98-kDa ectodomain of APP in the culture medium represents sAPP␣, as the BACE1 inhibitor C3 did not affect the level of sAPP; moreover, the ␣-secretase inhibitor, TAPI, reduced the levels of sAPP by 78 -85%.…”

Suppression of amyloid-β secretion from neurons bycis-9,trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid

“…CLA decrease Ab generation, we first assessed the level of b-site APP-cleaving enzyme (BACE1), which is the enzyme primarily responsible for amyloidogenic cleavage of APP (Vassar et al, 1999;Kimura et al, 2016). Because CLA alters expression of BACE1 but not ADAM10/asecretase in SH-SY5Y cells (Li et al, 2011), we examined protein expression of APP, BACE1, and presenilin 1 amino terminal fragment (PS1 NTF), a catabolic component of active g-secretase complex, in neurons treated with CLA and LA.…”

“…The remaining membrane-associated N-terminal region is subject to further processing by the carboxypeptidase-like activity of the gsecretase complex to generate various types of Ab with different carboxyl-terminal gcleaved sites, including the strongly neurotoxic and aggregation-prone Ab42 (Qi-Takahara et al, 2005;Takami & Funamoto 2012). Mutations of AD causative genes, including PSENs and APP, alter Ab generation (Mullan et al, 1992;Goate et al, 1991;Forman et al, 1997), and a protective Icelandic mutation of APP decreases b-cleavage and facilitates b'-cleavage of APP, thereby decreasing production of neurotoxic Ab1-40 and Ab1-42 (Jonsson et al, 2012;Kimura et al, 2016). Accordingly, Ab generation is considered to be a primary cause of AD.…”

Modulation of γ- and β-Secretases as Early Prevention Against Alzheimer’s Disease

“…BACE1 is abundant in brain, and in neurons in particular (63,64), and is the primary β-secretase responsible for Aβ production (65) as shown in numerous mouse knock out studies (66)(67)(68)(69) However, the effect on Aβ production is only 28% in heterozygous carriers (73). This mutation also affects the aggregation properties of Aβ (74,75) and induces alternative Bace1 cleavage at the β' site in APP, which might be protective (76). Thus although widely cited as genetic evidence supporting the notion that reducing β-secretase cleavage would benefit patients, the argument remains clearly circumstantial.…”