Glu11 Site Cleavage and N-Terminally Truncated Aβ Production upon BACE Overexpression

Liu, Kangning; Doms, Robert W.; Lee, Virginia M.‐Y.

doi:10.1021/bi015800g

Cited by 103 publications

(105 citation statements)

References 33 publications

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“…As expected based on a previous report (12), overexpression of BACE1 significantly increased the level of C89/CTF␤Ј (Fig. 5, A and B).…”

Section: Elevated Bace1 Activity Cleaves Ctf␤/c99 the Precursor Of Asupporting

confidence: 92%

“…Cells overexpressing BACE1 contained lower levels of CTF␤/C99 but dramatically higher levels of CTF␤Ј/C89 (Fig. 5C), indicating that CTF␤/C99 was cleaved again at the ␤Ј-site by elevated BACE1 activity, as reported (12). To confirm this conclusion, we analyzed A␤ species secreted from cells that did or did not overexpress BACE1 (Fig.…”

Section: Elevated Bace1 Activity Cleaves Ctf␤/c99 the Precursor Of Asupporting

confidence: 64%

“…8 and 40). Previous work showed that BACE1 also cleaves APP at the ␤Ј-site, but the biological significance of this reaction remained unclear because the ␤Ј-cleaved products of hAPP, CTF␤Ј/C89, and A␤(11-XX) are scarce relative to CTF␤/C99 and A␤(1-XX) (12,41). Along with previously reported data, our results confirm that mAPP is preferentially cleaved at the ␤Ј-site within the A␤ sequence and predominantly generates A␤(11-XX); by contrast, hAPP mostly generates A␤(1-XX) in vivo and in vitro (29 -31).…”

Section: Discussionmentioning

confidence: 99%

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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

Kimura¹,

Hata²,

Suzuki

2016

Journal of Biological Chemistry

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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-

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“…As expected based on a previous report (12), overexpression of BACE1 significantly increased the level of C89/CTF␤Ј (Fig. 5, A and B).…”

Section: Elevated Bace1 Activity Cleaves Ctf␤/c99 the Precursor Of Asupporting

confidence: 92%

Section: Elevated Bace1 Activity Cleaves Ctf␤/c99 the Precursor Of Asupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Kimura¹,

Hata²,

Suzuki

2016

Journal of Biological Chemistry

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“…␤-Amyloid-cleaving enzyme 1 (BACE1) is responsible of cleavages at position 1 and 11 of A␤ (28), and A␤ fragments starting with residue 3 were never reported when analysis of APP processing was carried out in vitro (29). However, in a double presenilin 1/APP mutant mice the A␤py3-42 form was detected (30), suggesting that in vivo BACE1 or another still unknown endoprotease might produce the cleavage at position 3.…”

Section: Discussionmentioning

confidence: 99%

β-Amyloid Is Different in Normal Aging and in Alzheimer Disease

Piccini

Russo

Gliozzi

et al. 2005

Journal of Biological Chemistry

189

161

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The mechanism of neurodegeneration caused by ␤-amyloid in Alzheimer disease is controversial. Neuronal toxicity is exerted mostly by various species of soluble ␤-amyloid oligomers that differ in their N-and C-terminal domains. However, abundant accumulation of ␤-amyloid also occurs in the brains of cognitively normal elderly people, in the absence of obvious neuronal dysfunction. We postulated that neuronal toxicity depends on the molecular composition, rather than the amount, of the soluble ␤-amyloid oligomers. Here we show that soluble ␤-amyloid aggregates that accumulate in Alzheimer disease are different from those of normal aging in regard to the composition as well as the aggregation and toxicity properties.A series of evidence indicates that progressive cerebral accumulation of ␤-amyloid (A␤), 2 a proteolytic product of transmembrane protein APP, is the primary pathogenic event of Alzheimer disease (AD) (1). Recent clues indicate that small, soluble A␤ aggregates produce more severe synaptic dysfunction and neuronal damage than do A␤ polymers (2-5). This behavior is common to all known pathogenic and nonpathogenic amyloidogenic peptides (6, 7). Soluble A␤ is detectable early in the cerebral cortex of subjects at risk for AD pathology, several years before the formation and deposition of amyloid fibrils (8). Hence, the analysis of soluble A␤ in brain tissue allows the characterization of the toxic form of the peptide.A strong argument against the amyloid hypothesis is the abundant and constant deposition of A␤ in the brains of elderly subjects, in the absence of signs of neuronal degeneration and dementia (9 -11). The reasons for the absence of pathogenic effect exerted by A␤ in normal aging are unknown. The issue has important therapeutic implications, because the major strategies to prevent and cure AD are focused on halting A␤ accumulation (12).In brains from Alzheimer disease (AD) and Down syndrome patients, three major species of soluble A␤ have been identified by mass spectrometry: the full-length form, A␤1-42, which has a relative molecular mass of 4.5 kDa, and two N-terminal peptides truncated at residue 3 (A␤3-42) and residue 11 (A␤11-42) with relative molecular masses of 4.2 and 3.5 kDa, respectively (13, 14). The 4.2-and 3.5-kDa bands are more prominent in familial AD carrying presenilin 1 mutations than in sporadic AD, suggesting that the ratio of soluble A␤ species may dictate the toxicity of the aggregates (15).We predicted that the composition of soluble A␤ underlies the different effect exerted by the molecule in AD and in normal aging. To investigate this hypothesis, we studied the composition and properties of aggregation and toxicity as well as the damage produced on artificial membranes of soluble A␤, comparing these areas in sporadic AD and cognitively normal elderly subjects with abundant amyloid plaques in cerebral cortex. MATERIALS AND METHODSTissues-We used frozen blocks and formalin-fixed sections of frontal cortex from 14 cases with late onset sporadic AD (mean age at death 80 Ϯ ...

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“…Indeed, it has been shown that overexpression of BACE1 strongly increases ␤-secretory cleavage of APP already in early secretory compartments (Capell et al, 2000;Liu et al, 2002;Lee et al, 2005), whereas under physiological expression levels, ␤-secretase cleavage of wild-type APP has been localized predominantly to endosomal/lysosomal compartments (Koo and Squazzo, 1994;Haass et al, 1995;Thinakaran et al, 1996). High overexpression of BACE1 was also shown to decrease A␤ levels in cell culture and transgenic mice by additional cleavages within A␤ (Fluhrer et al, 2002(Fluhrer et al, , 2003Liu et al, 2002;Lee et al, 2005). Thus, overexpression of BACE1 and aberrant cleavage of APP might have masked GGA-dependent effects on post-Golgi secretory and endocytic trafficking.…”

Section: Discussionmentioning

confidence: 99%

GGA1 Is Expressed in the Human Brain and Affects the Generation of Amyloid β-Peptide

Wahle¹,

Thal²,

Sastre³

et al. 2006

J. Neurosci.

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The ␤-amyloid peptide (A␤) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the ␤-amyloid precursor protein (APP) by ␤-secretase (BACE1) and ␥-secretase. BACE1 cleaves APP at the N terminus of the A␤ domain, generating a membrane-bound C-terminal fragment (CTF-␤) that can be subsequently cleaved by ␥-secretase within the transmembrane domain to release A␤. Because BACE1 initiates A␤ generation, it represents a potential target molecule to interfere with A␤ production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, ␥-ear-containing, ADP ribosylation factor-binding (GGA) proteins that are involved in the subcellular trafficking of BACE1. Here, we show that GGA1 is preferentially expressed in neurons of the human brain. GGA1 was also detected in activated microglia surrounding amyloid plaques in AD brains. Functional analyses with cultured cells demonstrate that GGA1 is implicated in the proteolytic processing of APP. Overexpression of GGA1 or a dominant-negative variant reduced cleavage of APP by BACE1 as indicated by a decrease in CTF-␤ generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of A␤. The modulation of APP processing by GGA1 is independent of a direct interaction of both proteins. Because total cellular activity of BACE1 was not affected by GGA1 expression, our data indicate that changes in the subcellular trafficking of BACE1 or other GGA1-dependent proteins contribute to changes in APP processing and A␤ generation. Thus, GGA proteins might be involved in the pathogenesis of AD.

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Glu11 Site Cleavage and N-Terminally Truncated Aβ Production upon BACE Overexpression

Cited by 103 publications

References 33 publications

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

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

β-Amyloid Is Different in Normal Aging and in Alzheimer Disease

GGA1 Is Expressed in the Human Brain and Affects the Generation of Amyloid β-Peptide

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