Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Deposition of amyloid beta (A beta) into extracellular plaques is a pathologic characteristic of Alzheimer's disease. Plasmin, neprilysin, endothelin-converting enzyme and insulin-degrading enzyme (IDE) have each been implicated in A beta degradation; data supporting the role of the latter three enzymes have included increased levels of endogenous murine A beta in mice genetically deficient for the respective enzyme. In this study, we sought to determine if plasminogen deficiency increases endogenous A beta. We report that plasminogen deficiency did not result in an A beta increase in the brain or in the plasma of adult mice. Hence, although plasmin is potentially important in the degradation of A beta aggregates, we interpret these data as suggesting that plasmin does not regulate steady-state A beta levels in non-pathologic conditions.
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PMID:Plasmin deficiency does not alter endogenous murine amyloid beta levels in mice. 1536 12

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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PMID:Abeta-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention. 1624 55

The deposition of beta-amyloid in the brain is a pathological hallmark of Alzheimer disease (AD). Normally, the accumulation of beta-amyloid is prevented in part by the activities of several degradative enzymes, including the endothelin-converting enzymes, neprilysin, insulin-degrading enzyme, and plasmin. Recent reports indicate that another metalloprotease, angiotensin-converting enzyme (ACE), can degrade beta-amyloid in vitro and in cellular overexpression experiments. In addition, ACE gene variants are linked to AD risk in several populations. Angiotensin-converting enzyme, neprilysin and endothelin-converting enzyme function as vasopeptidases and are the targets of drugs designed to treat cardiovascular disorders, and ACE inhibitors are commonly prescribed. We investigated the potential physiological role of ACE in regulating endogenous brain beta-amyloid levels for two reasons: first, to determine whether beta-amyloid degradation might be the mechanism by which ACE is associated with AD, and second, to determine whether ACE inhibitor drugs might block beta-amyloid degradation in the brain and potentially increase the risk for AD. We analyzed beta-amyloid accumulation in brains from ACE-deficient mice and in mice treated with ACE inhibitors and found that ACE deficiency did not alter steady-state beta-amyloid concentration. In contrast, beta-amyloid levels are significantly elevated in endothelin-converting enzyme and neprilysin knock-out mice, and inhibitors of these enzymes cause a rapid increase in beta-amyloid concentration in the brain. The results of these studies do not support a physiological role for ACE in the degradation of beta-amyloid in the brain but confirm roles for endothelin-converting enzyme and neprilysin and indicate that reductions in these enzymes result in additive increases in brain amyloid beta-peptide levels.
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PMID:Regulation of steady-state beta-amyloid levels in the brain by neprilysin and endothelin-converting enzyme but not angiotensin-converting enzyme. 1691 50

Extensive beta-amyloid (A beta) deposits in brain parenchyma in the form of senile plaques and in blood vessels in the form of amyloid angiopathy are pathological hallmarks of Alzheimer's disease (AD). The mechanisms underlying A beta deposition remain unclear. Major efforts have focused on A beta production, but there is little to suggest that increased production of A beta plays a role in A beta deposition, except for rare familial forms of AD. Thus, other mechanisms must be involved in the accumulation of A beta in AD. Recent data shows that impaired clearance may play an important role in A beta accumulation in the pathogenesis of AD. This review focuses on our current knowledge of A beta-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), insulin-degrading enzyme (IDE), angiotensin-converting enzyme (ACE), and the plasmin/uPA/tPA system as they relate to amyloid deposition in AD.
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PMID:beta-Amyloid degradation and Alzheimer's disease. 1704 8

Considerable evidence indicates that the amyloid-beta (Abeta) peptide, a proteolytic fragment of the amyloid precursor protein, is the pathogenic agent in Alzheimer's disease (AD). A number of proteases have been reported as capable of degrading Abeta, among them: neprilysin, insulin-degrading enzyme, endothelin-converting enzyme-1 and -2, angiotensin-converting enzyme and plasmin. These proteases, originating from a variety of cell types, degrade Abeta of various conformational states and in different cellular locations. We report here the isolation of a serine protease from serum-free conditioned medium of human neuroblastoma cells. Tandem mass spectrometry (MS/MS)-based sequencing of the isolated protein identified acyl peptide hydrolase (APH; EC3.4.19.1) as the active peptidase. APH is one of four members of the prolyl oligopeptidase family of serine proteases expressed in a variety of cells and tissues, including erythrocytes, liver and brain, but its precise biological activity is unknown. Here, we describe the identification of APH as an Abeta-degrading enzyme, and we show that the degradation of Abeta by APH isolated from transfected cells is inhibited by APH-specific inhibitors, as well as by synthetic Abeta peptide. In addition, we cloned APH from human brain and from neuroblastoma cells. Most importantly, our results indicate that APH expression in AD brain is lower than in age-matched controls.
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PMID:Acyl peptide hydrolase, a serine proteinase isolated from conditioned medium of neuroblastoma cells, degrades the amyloid-beta peptide. 1724 Nov 60

Proteolytic enzymes constitute around 2% of the human genome and are involved in many stages of cell development from fertilization to death (apoptosis). The identification of many novel proteases from genome-sequencing programs has suggested them as potential new therapeutic targets. In addition, several well-characterized metallopeptidases were recently shown to possess new biological roles in neuroinflammation and neurodegeneration. As a result of these studies, metabolism of the neurotoxic and inflammatory amyloid peptide (Abeta) is considered as a physiologically relevant process with several metallopeptidases being suggested for the role of amyloid-degrading enzymes. These include the neprilysin (NEP) family of metalloproteinases (including its homologue endothelin-converting enzyme), insulin-degrading enzyme, angiotensin-converting enzyme, plasmin, and, possibly, some other enzymes. NEP also has a role in metabolism of sensory and inflammatory neuropeptides such as tachykinins and neurokinins. The existence of natural enzymatic mechanisms for removal of amyloid peptides has extended the therapeutic avenues in Alzheimer's disease (AD) and neurodegeneration. The proteolytic events underlying AD are highly compartmentalized in the cell and formation of amyloid peptide from its precursor molecule APP (amyloid precursor protein) takes place both within intracellular compartments and in the plasma membrane, especially in lipid raft domains. Degradation of amyloid peptide by metallopeptidases can also be both intra- and extracellular depending on the activity of membrane-bound enzymes and their soluble partners. Soluble forms of proteases can be secreted or released from the cell surface through the activity of "sheddases"-another group of proteolytic enzymes involved in key cellular regulatory functions. The activity of proteases involved in amyloid metabolism depends on numerous factors (e.g., genetic, environmental, age), and some conditions (e.g., hypoxia and ischemia) shift the balance of amyloid metabolism toward accumulation of higher concentrations of Abeta. In this regard, regulation of the activity of amyloid-degrading enzymes should be considered as a viable strategy in neuroprotection.
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PMID:New insights into the roles of metalloproteinases in neurodegeneration and neuroprotection. 1767 58

In Alzheimer's disease (AD) Abeta accumulates because of imbalance between the production of Abeta and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of Abeta is partly, if not in some cases solely, because of defects in its removal--mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading Abeta. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced Abeta-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading Abetain vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOEepsilon4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to Abeta plaque load. Up-regulation of some Abeta-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other Abeta-clearance pathways, reductions in the activity of particular Abeta-degrading enzymes may become critical, leading to the development of AD and CAA.
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PMID:Abeta-degrading enzymes in Alzheimer's disease. 1836 35

The steady state concentration of the Alzheimer's amyloid-beta peptide in the brain represents a balance between its biosynthesis from the transmembrane amyloid precursor protein (APP), its oligomerisation into neurotoxic and stable species and its degradation by a variety of amyloid-degrading enzymes, principally metallopeptidases. These include, among others, neprilysin (NEP) and its homologue endothelin-converting enzyme (ECE), insulysin (IDE), angiotensin-converting enzyme (ACE) and matrix metalloproteinase-9 (MMP-9). In addition, the serine proteinase, plasmin, may participate in extracellular metabolism of the amyloid peptide under regulation of the plasminogen-activator inhibitor. These various amyloid-degrading enzymes have distinct subcellular localizations, and differential responses to aging, oxidative stress and pharmacological agents and their upregulation may provide a novel and viable therapeutic strategy for prevention and treatment of Alzheimer's disease. Potential approaches to manipulate expression levels of the key amyloid-degrading enzymes are highlighted.
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PMID:Amyloid-degrading enzymes as therapeutic targets in Alzheimer's disease. 1839 6