Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease

Funalot, Benoît; Ouimet, Tanja; Clapéron, Audrey; Fallet, C.; Delacourte, André; Epelbaum, Jacques; Subkowski, Thomas; Léonard, Nadine; Codron, Valérie; David, J.-P.; Amouyel, Philippe; Jc, Schwartz; Helbecque, Nicole

doi:10.1038/sj.mp.4001584

Cited by 57 publications

(23 citation statements)

References 47 publications

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“…Both ECE-1 and ECE-2 are expressed in the brain in regions that are relevant to AD pathology [39,40]. To determine the physiological relevance of ECE-mediated Aβ cleavage, the level of endogenous Aβ was examined in the brains of ECE-1 and ECE-2-knockout mice.…”

Section: Ece-1 and Ece-2 Contribute To The Regulation Of Steady-statementioning

confidence: 99%

Aβ-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention

Eckman

2005

Biochem. Soc. Trans

154

132

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The accumulation of Abeta (amyloid beta-protein) peptides in the brain is a pathological hallmark of all forms of AD (Alzheimer's disease) and reducing Abeta levels can prevent or reverse cognitive deficits in mouse models of the disease. Abeta is produced continuously and its concentration is determined in part by the activities of several degradative enzymes, including NEP (neprilysin), IDE (insulin-degrading enzyme), ECE-1 (endothelin-converting enzyme 1) and ECE-2, and probably plasmin. Decreased activity of any of these enzymes due to genetic mutation, or age- or disease-related alterations in gene expression or proteolytic activity, may increase the risk for AD. Conversely, increased expression of these enzymes may confer a protective effect. Increasing Abeta degradation through gene therapy, transcriptional activation or even pharmacological activation of the Abeta-degrading enzymes represents a novel therapeutic strategy for the treatment of AD that is currently being evaluated in cell-culture and animal models. In this paper, we will review the roles of NEP, IDE, ECE and plasmin in determining endogenous Abeta concentration, highlighting recent results concerning the regulation of these enzymes and their potential as therapeutic targets.

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Section: Ece-1 and Ece-2 Contribute To The Regulation Of Steady-statementioning

confidence: 99%

Aβ-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention

Eckman

2005

Biochem. Soc. Trans

154

132

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“…The in vivo function of ECE has been examined in ECE-1-and ECE-2-deficient mice and, in both cases, levels of A␤ were increased compared with WT mice, indicating that these ECEs are A␤-degrading enzymes in vivo (8). However, it is not yet known whether stimulation of ECE activity can reduce A␤ levels or plaque-associated AD pathology, although in one association study, a genetic variant of human ECE1 (ECE1B C-338A) that shows increased promoter activity was associated with a reduced risk of sporadic AD in a French Caucasian population (9). Several in vitro cell culture studies that have examined phorbol ester-stimulated secretion of APP fragments suggest that PKC␣ and PKC stimulate ␣-secretase activity (10 -14), although only PKC also has been shown to reduce A␤ levels in vitro (15).…”

mentioning

confidence: 99%

PKCε increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice

Choi

Wang

et al. 2006

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

112

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Deposition of plaques containing amyloid ␤ (A␤) peptides is a neuropathological hallmark of Alzheimer's disease (AD).Here we demonstrate that neuronal overexpression of the isozyme of PKC decreases A␤ levels, plaque burden, and plaque-associated neuritic dystrophy and reactive astrocytosis in transgenic mice expressing familial AD-mutant forms of the human amyloid precursor protein (APP). Compared with APP singly transgenic mice, APP͞PKC doubly transgenic mice had decreased A␤ levels but showed no evidence for altered cleavage of APP. Instead, PKC overexpression selectively increased the activity of endothelin-converting enzyme, which degrades A␤. The activities of other A␤-degrading enzymes, insulin degrading enzyme and neprilysin, were unchanged. These results indicate that increased neuronal PKC activity can promote A␤ clearance and reduce AD neuropathology through increased endothelin-converting enzyme activity.Alzheimer's disease ͉ phosphorylation ͉ proteolysis ͉ neurodegeneration A lzheimer's disease (AD) is the most common cause of dementia in the elderly and is characterized pathologically by the deposition of senile plaques containing amyloid ␤ (A␤) peptides in the brain (1). A␤ is composed primarily of 40-and 42-aa peptides produced from the ␤-amyloid precursor protein (APP) through the combined proteolytic actions of ␤-and ␥-secretase. In cultured cells, treatment with tumor-promoting phorbol esters that activate several PKC isozymes reduces A␤ levels through a mechanism that may involve ␣-secretasemediated cleavage of APP (2, 3). However, although intraparenchymal administration of phorbol esters reduces A␤ levels and deceases amyloid plaque density in mice expressing an amyloidogenic variant of human APP, it does not increase ␣-secretase activity in the brain (4). This finding raises the possibility that PKC decreases A␤ levels in vivo by other mechanisms. Such mechanisms might involve reductions in the activity of amyloidogenic proteases such as BACE1 and ␥-secretase (5).A␤ accumulation is influenced not only by enzymes responsible for its production but also by mechanisms involved in its clearance (5). Several proteases that degrade A␤ in mice include insulin-degrading enzyme (IDE), neprilysin (NEP), and endothelin-coverting enzyme (ECE) 1 and 2 (6). Recently, Leissring et al. (7) demonstrated that transgenic overexpression of IDE or NEP in neurons significantly reduces A␤ levels and plaqueassociated AD pathology. The in vivo function of ECE has been examined in ECE-1-and ECE-2-deficient mice and, in both cases, levels of A␤ were increased compared with WT mice, indicating that these ECEs are A␤-degrading enzymes in vivo (8). However, it is not yet known whether stimulation of ECE activity can reduce A␤ levels or plaque-associated AD pathology, although in one association study, a genetic variant of human ECE1 (ECE1B C-338A) that shows increased promoter activity was associated with a reduced risk of sporadic AD in a French Caucasian population (9). Several in vitro cell culture studies that hav...

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“…Although the ECEs have been suggested to play a role in Alzheimer disease and ␤-amyloid clearance (23)(24)(25), their true physiological functions in these processes have been difficult to assess. ECE-2 has been identified as a possible specific marker of Alzheimer disease-type dementia in an unbiased screen where it was found to be the most down-regulated gene in human parietal lobe of Alzheimer patients (26).…”

Section: Discussionmentioning

confidence: 99%

“…These three metalloproteases have been shown to influence endogenous A␤ levels in the brains of their respective knock-out mice (22,23), and a human polymorphism of the human ECE-1 gene has been linked to Alzheimer disease (25). Lastly, the expression of the ECE-2 gene was recently found to be the most down-regulated in an unbiased microarray screen of the gene expression in the inferior parietal lobe of late onset Alzheimer disease patients compared with non-Alzheimer disease-associated dementia and nondemented controls (26).…”

Section: Endothelin-converting Enzyme-2 (Ece-2)mentioning

confidence: 99%

Identification of an Endothelin-converting Enzyme-2-specific Fluorigenic Substrate and Development of an in Vitro and ex Vivo Enzymatic Assay

Ouimet

Orng

Poras

et al. 2010

Journal of Biological Chemistry

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Endothelin-converting enzyme-2 (ECE-2) is a membranebound zinc-dependent metalloprotease that shares a high degree of sequence homology with ECE-1, but displays an acidic pH optimum characteristic of maturing enzymes acting late in the secretory pathway. Although ECE-2, like ECE-1, can cleave the big endothelin intermediate to produce the vasoconstrictive endothelin peptide, its true physiological function remains to be elucidated, a task that is hampered by the lack of specific tools to study and discriminate ECE-2 from ECE-1, i.e. specific substrates and/or specific inhibitors. To fill this gap, we searched for novel ECE-specific peptide substrates. To this end, peptides derived from the big endothelin intermediate were tested using ECE-1 and ECE-2, leading to the identification of an ECE-1-specific substrate. Moreover, screening of our proprietary fluorigenic peptide Fluofast libraries using ECE-1 and ECE-2 allowed the identification of Ac-SKG-Pya-F-W-Nop-GGK-NH 2 (PL405), as a specific and high affinity ECE-2 substrate. Indeed, ECE-2 cleaved PL405 at the Pya-F amide bond with a specificity constant (k cat /K m ) of 8.1 ؎ 0.9 ؋ 10 3 M ؊1 s ؊1 . Using this novel substrate, we also characterized the first potent (K i ‫؍‬ 7.7 ؎ 0.3 nM) and relatively selective ECE-2 inhibitor and developed a quantitative fluorigenic ECE-2 assay. The assay was used to study the ex vivo ECE-2 activity in wild type and ECE-2 knockout tissues and was found to truly reflect ECE-2 expression patterns. The PL405 assay is thus the first tool to study ECE-2 inhibition using high throughput screening or for ex vivo ECE-2 quantification.Endothelin-converting enzyme-2 (ECE-2) 2 is a zinc-dependant metalloprotease belonging to the M13 family, in which it shares the highest degree of sequence homology with ECE-1 (EC 3.4.24.71) (1, 2). The family is also constituted by neprilysin (NEP, EC 3.4.24.11) (3); damage-induced neuronal endopeptidase, also known as endothelin converting enzyme like (ECEL) (4, 5); the Kell blood group antigen (6); phosphate-regulating neutral endopeptidase on the X chromosome (7); and neprilysin 2 (NEP2) (8 -11). These peptidases are type II integral membrane glycoproteins composed of a small cytosolic tail followed by a transmembrane region and a large C-terminal core that is typically exposed at the cell surface. The active site of the enzyme is located within this last domain and is characterized by two highly conserved zinc-binding consensus motifs HEXXH and EXXXD (where X is any amino acid) (12). The structure of the human ECE-1 enzyme co-crystallized with phosphoramidon, a generic inhibitor of the family, was recently reported (13) showing the conserved "thermolysin-like" arrangement of its catalytic site (14, 15).The endothelin-converting enzymes were first characterized as cleaving the big endothelin inactive intermediate at its Trp 21 -Val 22 bond to produce the highly vasoconstrictive endothelin peptide (1, 2). It was thereafter found that ECE-1 can also hydrolyze smaller peptides in vitro such as big endothel...

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Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease

Cited by 57 publications

References 47 publications

Aβ-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention

Aβ-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention

PKCε increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice

Identification of an Endothelin-converting Enzyme-2-specific Fluorigenic Substrate and Development of an in Vitro and ex Vivo Enzymatic Assay

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