Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A synthetic peptide corresponding to the first 28 amino acids of the Alzheimer disease amyloid beta/A4 peptide (3.2 kDa) aggregated to a high molecular weight (15 kDa) on SDS/urea polyacrylamide gels. Proteinase K, V8 protease, trypsin, and endopeptidase Lys-C readily degraded the aggregate. By contrast, when digested by endopeptidase Arg-C, a new polypeptide aggregate of higher molecular weight (16 kDa) was observed on denaturing gels without degraded smaller products. The new aggregate was comprised of three peptides: an intact beta/A4(1-28) and partially degraded peptides beta/A4(1-5) plus beta/A4(6-28). The results were confirmed by treatment of beta/A4 with other arginine-specific proteases: the gamma subunit of nerve growth factor and clostripain. The results indicate that arginine-specific proteases, including a growth factor processing enzyme, can nick aggregated beta/A4(1-28) amyloid and alter the configuration to produce a more complex aggregated form. If similar highly specific proteolytic mechanisms occur in the Alzheimer disease brain, the processing may promote the formation of high molecular weight aggregates that contribute to the development of relatively insoluble senile plaque core protein.
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PMID:Arginine specific endopeptidases modify the aggregation properties of a synthetic peptide derived from Alzheimer beta/A4 amyloid. 151 20

The cerebral deposition of amyloid beta-peptide (A beta) is a histopathological characteristic of Alzheimer's disease. Because an impaired clearance of A beta might be involved in the disease, we investigated the proteolytic degradation of synthetic A beta (40-residue peptide) in cultures of glial cells and characterized a protease involved. Whereas rat astrocytes had a very low degradation capacity, cultivated rat microglia cells cleaved A beta. Microglia activity was considerably enhanced by stimulation with lipopolysaccharide and to a lesser extent by phorbol esters. Most of the A beta-degrading activity was released into the medium. By use of selective inhibitors the protease was characterized as a metalloprotease of approximately 200 kDa that was different from neutral endopeptidase (a neuropeptide-degrading enzyme), matrix metalloproteases, or macrophage elastase. Its activity was efficiently reduced by four hydroxamic acid-based zinc-metalloprotease inhibitors that have been shown to inhibit membrane protein secretases (disintegrins). We conclude that activated microglia cells might impair amyloid plaque formation by release of a metalloprotease that degrades soluble A beta, before polymerization.
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PMID:Proteolytic degradation of Alzheimer's disease amyloid beta-peptide by a metalloproteinase from microglia cells. 945 67

Alzheimer amyloid beta-peptide (Abeta) is a physiological peptide constantly anabolized and catabolized under normal conditions. We investigated the mechanism of catabolism by tracing multiple-radiolabeled synthetic peptide injected into rat hippocampus. The Abeta1-42 peptide underwent full degradation through limited proteolysis conducted by neutral endopeptidase (NEP) similar or identical to neprilysin as biochemically analyzed. Consistently, NEP inhibitor infusion resulted in both biochemical and pathological deposition of endogenous Abeta42 in brain. This NEP-catalyzed proteolysis therefore limits the rate of Abeta42 catabolism, up-regulation of which could reduce the risk of developing Alzheimer's disease by preventing Abeta accumulation.
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PMID:Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. 1088 92

To identify the amyloid beta peptide (Abeta) 1-42-degrading enzyme whose activity is inhibited by thiorphan and phosphoramidon in vivo, we searched for neprilysin (NEP) homologues and cloned neprilysin-like peptidase (NEPLP) alpha, NEPLP beta, and NEPLP gamma cDNAs. We expressed NEP, phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PEX), NEPLPs, and damage-induced neuronal endopeptidase (DINE) in 293 cells as 95- to 125-kDa proteins and found that the enzymatic activities of PEX, NEPLP alpha, and NEPLP beta, as well as those of NEP and DINE, were sensitive to thiorphan and phosphoramidon. Among the peptidases tested, NEP degraded both synthetic and cell-secreted Abeta1-40 and Abeta1-42 most rapidly and efficiently. PEX degraded cold Abeta1-40 and NEPLP alpha degraded both cold Abeta1-40 and Abeta1-42, although the rates and the extents of the digestion were slower and less efficient than those exhibited by NEP. These data suggest that, among the endopeptidases whose activities are sensitive to thiorphan and phosphoramidon, NEP is the most potent Abeta-degrading enzyme in vivo. Therefore, manipulating the activity of NEP would be a useful approach in regulating Abeta levels in the brain.
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PMID:Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases. 1127 16

In the pathological process of Alzheimer's disease (AD), deposition of amyloid beta-peptide (A beta) in the brain parenchyma plays an important role. Neprilysin (NEP), a neutral endopeptidase, degrades A beta, and it is postulated that decreased NEP activity may contribute to the development of AD by promoting the accumulation of A beta. The human NEP gene possesses four dinucleotide repeat polymorphisms, and it is possible that these polymorphisms regulate the NEP expression levels and influence the pathological cascade of AD. Therefore, we investigated the association of these polymorphisms with AD. We performed genotyping of each polymorphism in 201 Japanese sporadic AD patients and 208 Japanese controls. There were no significant differences between the AD and control groups in allele frequencies of each polymorphism. We conclude that these polymorphisms in the NEP gene do not contribute to genetic risk factors for sporadic AD.
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PMID:Dinucleotide repeat polymorphisms in the neprilysin gene are not associated with sporadic Alzheimer's disease. 1184 75

The steady-state level of amyloid beta-peptide (Abeta) represents a balance between its biosynthesis from the amyloid precursor protein (APP) through the action of the beta- and gamma-secretases and its catabolism by a variety of proteolytic enzymes. Recent attention has focused on members of the neprilysin (NEP) family of zinc metalloproteinases in amyloid metabolism. NEP itself degrades both Abeta(1-40) and Abeta(1-42) in vitro and in vivo, and this metabolism is prevented by NEP inhibitors. Other NEP family members, for example endothelin-converting enzyme, may contribute to amyloid catabolism and may also play a role in neuroprotection. Another metalloproteinase, insulysin (insulin-degrading enzyme) has also been advocated as an amyloid-degrading enzyme and may contribute more generally to metabolism of amyloid-forming peptides. Other candidate enzymes proposed include angiotensin-converting enzyme, some matrix metalloproteinases, plasmin and, indirectly, thimet oligopeptidase (endopeptidase-24.15). This review critically evaluates the evidence relating to proteinases implicated in amyloid catabolism. Therapeutic strategies aimed at promoting A,beta degradation may provide a novel approach to the therapy of Alzheimer's disease.
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PMID:Beta-amyloid catabolism: roles for neprilysin (NEP) and other metallopeptidases? 1206 22

Quercetin and resveratrol are weak inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) activity of the neuroblastoma cell line SK-N-SH. The long term incubation of the cells for 4 days with quercetin, resveratrol and a combination of both substances in concentrations lower than necessary for inhibition of NEP and ACE activity induced the cellular enzyme activity of NEP and ACE associated with an inhibition of cellular proliferation. The long term treatment of neuroblastoma cells with quercetin and resveratrol enhanced the differentiation state of the cells. Taking into account the significance of NEP and ACE for the degradation of amyloid beta peptides, the effect of quercetin and resveratrol as constituents of red wine for a neuroprotective activity is discussed.
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PMID:Induction of neutral endopeptidase and angiotensin-converting enzyme activity of SK-N-SH cells in vitro by quercetin and resveratrol. 1222 97

Molecular, genetic, and pharmacological studies have shown that neprilysin (also called NEP) catabolizes amyloid beta peptides (A beta) in healthy conditions. However, in Alzheimer disease (AD), A beta accumulates forming senile plaques in brain parenchyma and amyloid deposition around blood vessels. In this study, we tested at cellular level the relationship between neprilysin and A beta in human healthy and AD brain. Our results provided evidence for declining levels of neprilysin in AD brains as compared to healthy controls in parallel with increasing deposition of A beta. In hippocampus of AD individuals we observed a significant down-regulation of neprilysin expression in pyramidal neurons, consistent with the possibility that neprilysin controls the level of A beta accumulation and plaque formation in this area. In the cortex and leptomeninges, neprilysin was expressed in the smooth muscle cells of blood vessels. In sections from AD patients we observed a clear inverse relationship between neprilysin and A beta peptide levels in the vasculature, implicating neprilysin in cerebral amyloid angiopathy.
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PMID:Declining expression of neprilysin in Alzheimer disease vasculature: possible involvement in cerebral amyloid angiopathy. 1238 51

The Dutch, Flemish, Italian, and Arctic mutations in the amyloid precursor protein (APP) gene encode changes within the sequence of the amyloid beta peptide (Abeta) and cause presenile cerebral amyloid angiopathy, cerebral parenchymal amyloidosis, or both. These disorders are caused by accumulation of Abeta, with no evidence of increased Abeta production. Our results showed that these mutations in Abeta make it resistant to proteolytic degradation by neprilysin, the peptidase with the most important role in catabolism of Abeta in the brain. These mutations in Abeta could thus be pathogenic not only by facilitating fibrillogenesis but also by extending the half-life of Abeta in the brain.
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PMID:Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation. 1280 42

Green tea extract (EFLA85942) is able to induce specifically the neutral endopeptidase (NEP) activity and to inhibit the proliferation of SK-N-SH cells; the angiotensin-converting enzyme (ACE) activity is not influenced under the same conditions. The treatment of the cells with arabinosylcytosine and green tea extract results in a strong enhancement of cellular NEP activity whereas cellular ACE activity was not changed significantly, indicating a green tea extract-specific regulation of NEP expression. Because of its role in the degradation of amyloid beta peptides this enzyme induction of NEP by long term treatment with green tea extract may have a beneficial effect regarding the prevention of forming amyloid plaques.
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PMID:Enhancement of neutral endopeptidase activity in SK-N-SH cells by green tea extract. 1367 33


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