Signature Amyloid β Profiles Are Produced by Different γ-Secretase Complexes

Acx, Hermien; Chávez‐Gutiérrez, Lucía; Serneels, Lutgarde; Lismont, Sam; Benurwar, Manasi; Elad, Nadav; Strooper, Bart De

doi:10.1074/jbc.m113.530907

Cited by 80 publications

(95 citation statements)

References 47 publications

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“…hPS2 appears to reduce the endopeptidase activity of γ-secretase (e sites) compared with hPS1, and Aph-1 variants affect the carboxypeptidase-like activities (γ-sites) (11). In this study, we demonstrate that the enzymatic properties of PSH closely resemble those of the most abundant γ-secretase complex that comprises hPS1, Pen-2, Aph-1A, and nicastrin.…”

Section: Discussionmentioning

confidence: 55%

“…It remains to be investigated to what extent PSH can be compared with the other three distinct γ-secretase complexes. Regardless of the outcome of these investigations, the use of a single protease PSH as a surrogate no longer allows assessment of the impact on Aβ generation by two related γ-secretases, each with a different variant subunit (such as Aph-1A versus Aph-1B) (11).…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that the human γ-secretase comes in four different forms, each with a different Aβ cleavage profile (11). hPS2 appears to reduce the endopeptidase activity of γ-secretase (e sites) compared with hPS1, and Aph-1 variants affect the carboxypeptidase-like activities (γ-sites) (11).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, PSH may represent an attractive surrogate of γ-secretase for modulator screening if PSH cleaves APP C99 and such cleavages recapitulate those by the intact γ-secretase. Notably, due to the presence of two different presenilin variants (hPS1 and hPS2) and two Aph-1 variants (Aph-1A and Aph-1B), there are at least four distinct human γ-secretase complexes, which exhibit different signature Aβ profiles (11). In this study, we compare PSH to the most prevalent γ-secretase complex comprising hPS1 and Aph-1A.…”

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confidence: 99%

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Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH

Dang

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant cleavage of amyloid precursor protein (APP) by γ-secretase contributes to the development of Alzheimer's disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of γ-secretase), making modulation of γ-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact γ-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to γ-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into Aβ42, Aβ40, and Aβ38. The molar ratio of the cleavage products Aβ42 over Aβ40 by PSH is nearly identical to that by γ-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of γ-secretase also modulate PSH similarly in terms of the Aβ42/Aβ40 ratio. Structural analysis reveals association of a known γ-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of γ-secretase.A myloid precursor protein (APP) is initially cleaved by β-secretase in the extracellular space, producing a membrane-tethered, 99-residue carboxyl-terminal fragment known as APP C99 (1). APP C99 then undergoes sequential cleavages by γ-secretase, first at the e sites, yielding Aβ49/Aβ48, and eventually at the γ-sites, generating Aβ42/Aβ40/Aβ38 (2-4) (Fig. 1A). The 230-kDa γ-secretase contains four components: presenilin (PS), Pen-2, Aph-1, and nicastrin (NCT), of which PS1 is the target of most mutations derived from early-onset familial Alzheimer's disease (FAD) patients. Rather than abolishing the protease activity of γ-secretase, these mutations are thought to increase the molar ratio of Aβ42 over Aβ40 (2).Among the cleavage products of γ-secretase, Aβ42 is particularly prone to aggregation, leading to formation of β-amyloid plaque in the brain and presumably causing Alzheimer's disease (3). Other FAD-derived mutations map to APP and PS2, lending support to the causal relationship between formation of β-amyloid plaque and Alzheimer's disease (5). Therapeutic intervention of Alzheimer's disease may directly benefit from in vitro investigation of γ-secretase and discovery of its potential modulators (6). Unfortunately, such effort has been hampered by the difficulty in expression, purification, and manipulation of the complex protease. This problem persists despite recent breakthroughs in structural elucidation of γ-secretase and nicastrin (7,8).The intramembrane aspartate protease PSH from the archaeon Methanoculleus marisnigri JR1 shares 19% sequence identity and 53% sequence similarity with human PS1 (hPS1). The signature motifs for catalysis, ΦYDΦΦ (Φ for a hydrophobic residue) on transmembrane segment 6 (TM6) and ΦGΦGD on TM7, are identical between PSH and hPS1. PSH can be readily overexpressed in Escheri...

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH

Dang

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Pen2 has two TMDs and is thought to be important for triggering presenilin self-cleavage (5,6). Little is known about the biochemical function of the seven-TMD Aph-1 other than that it is required for complex formation and full maturation of γ-secretase, although a recent study suggests a role in determining the length of Aβ peptide proteolytic products (7). The fourth component of the complex, nicastrin, is a single-TMD protein with a large ectodomain.…”

mentioning

confidence: 99%

Structure of nicastrin unveils secrets of γ-secretase

Bolduc

Wolfe

2014

Proc. Natl. Acad. Sci. U.S.A.

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Despite afflicting tens of millions worldwide, Alzheimer's disease (AD) remains a devastating brain-destroying malady with no effective treatment or cure. A central hallmark of AD is the deposition of amyloid plaques in the brain. These plaques are primarily composed of the amyloid β-peptide (Aβ), a byproduct of proteolytic processing of the amyloid precursor protein (APP) within its transmembrane domain by γ-secretase. Mutations in both APP and presenilin, the catalytic component of γ-secretase, are associated with dominant early-onset AD, highlighting their central importance in pathogenesis (1). Gaining a detailed mechanistic understanding of how γ-secretase processes APP-and its other substrates, such as Notch receptorsis critically important for biology and medicine (2). Despite a wealth of biochemical studies, key details of how γ-secretase functions have remained elusive because of a lack of high-resolution structural data. In PNAS, Xie et al. present a crystal structure of nicastrin, the first atomic-resolution structure of a component of a γ-secretase complex (3).The membrane-embedded γ-secretase complex is comprised of four proteins that are necessary and sufficient for its activity: Presenilin, Pen-2, Aph-1, and nicastrin (4). Presenilin, an aspartyl protease, contains catalytic aspartates on transmembrane domains (TMDs) 6 and 7 of its nine TMD helices. Upon assembly of the four components within the endoplasmic reticulum, presenilin undergoes autoproteolysis between TMDs 6 and 7 to form catalytically active γ-secretase. Pen2 has two TMDs and is thought to be important for triggering presenilin self-cleavage (5, 6). Little is known about the biochemical function of the seven-TMD Aph-1 other than that it is required for complex formation and full maturation of γ-secretase, although a recent study suggests a role in determining the length of Aβ peptide proteolytic products (7). The fourth component of the complex, nicastrin, is a single-TMD protein with a large ectodomain.γ-Secretase is a member of a broader family of intramembrane-cleaving proteases, which include the site 2 protease (S2P) family of metalloproteases and the rhomboid family of serine proteases (8). Unlike S2P and rhomboid, whose high-resolution structures were solved some years ago, detailed structural information of γ-secretase has been slow to develop. Until recently, the only structural information known about γ-secretase has been gleaned from low-resolution (∼12 Å at best) electron microscopy (EM) studies. With the advent of advanced cryo-EM techniques and equipment, a much more detailed structure of the complex was recently obtained (9). Although the resolution of this structure is still too poor to see atomic details, the overall architecture of the complex was visualized for the first time. Individual TMDs could be seen, although not assigned with certainty to each component of the complex. The most well-resolved portion of the complex was the ectodomain of nicastrin, although all of the glycosylation sites and several long segme...

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The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1

Liu,

Schultz,

Saba

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONThough recognized as a potential cause of autosomal dominant Alzheimer's disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared amyloid beta (Aβ) production across all missense PSEN2 variants in the AlzForum database and, when possible, to corresponding PSEN1 variants.METHODSWe expressed 74 PSEN2 variants, 21 of which had known, homologous PSEN1 pathogenic variants with the same amino acid substitution, in HEK293 cells lacking presenilin 1/2. Aβ production was compared to age at symptom onset (AAO) and between PSEN1/2 homologs.RESULTSAβ42/40 and Aβ37/42 ratios correlated with AAO across all PSEN2 variants, strongly driven by the subset of PSEN2 variants with PSEN1 homologs. Aβ production across PSEN1/2 homologs was highly correlated. PSEN2 AAO correlated with AAO in PSEN1 homologs but was an average of 18.3 years later.DISCUSSIONThe existence of a PSEN1 homolog and patterns of Aβ production are important considerations in assessing the pathogenicity of previously reported and new PSEN2 variants.Highlights There were associations between the patterns of amyloid beta (Aβ) production across presenilin 2 (PSEN2) variants and age at symptom onset (AAO). PSEN2 variants for which there is a known, corresponding variant in presenilin 1 (PSEN1) are more likely to have abnormal Aβ production patterns that strongly correlate with AAO, compared to those that lack a known PSEN1 counterpart (“non‐homologous PSEN2 variants”). Most PSEN2 variants lacking PSEN1 counterparts had Aβ42/40 ratios close to those of wild‐type PSN2, arguing against their pathogenicity. Homologous PSEN1 and PSEN2 variants had correlated Aβ42/40 and Aβ37/42 ratios, indicating that the corresponding amino acid substitution in each presenilin may have largely similar biochemical effects on γ‐secretase processivity.

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Signature Amyloid β Profiles Are Produced by Different γ-Secretase Complexes

Cited by 80 publications

References 47 publications

Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH

Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH

Structure of nicastrin unveils secrets of γ-secretase

The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1

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