Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.56 (insulin-degrading enzyme)
 737 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The beta amyloid (Abeta) cascade has been at the forefront of the hypothesis used to describe the pathogenesis of Alzheimer's disease (AD). It is generally accepted that drugs that can regulate the processing of the amyloid precursor protein (APP) toward the non-amyloidogenic pathway may have a therapeutic potential. Previous studies have shown that protein kinase C (PKC) hypofunction has an important role in AD pathophysiology. Therefore, the effects of a new PKC activator, alpha-APP modulator [(2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (TPPB)], on APP processing were investigated. Using PC12 cells and SH-SY5Y(APP695) cells, it was found that TPPB promoted the secretion of sAPPalpha without affecting full-length expression of APP. The increase in sAPPalpha by TPPB was blocked by inhibitors of PKC, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and tyrosine kinase, suggesting the involvement of these signal transduction pathways. TPPB increased alpha-secretase activity [a disintegrin and metalloproteinase (ADAM)10 and 17], as shown by direct fluorescence activity detection and Western blot analysis. TPPB-induced sAPPalpha release was blocked by the metalloproteinase inhibitor TAPI-2, furin inhibitor CMK and by the protein-trafficking inhibitor brefeldin. The results also showed that TPPB decreased beta-secretase activity, Abeta40 release and beta site APP-cleaving enzyme 1 (BACE1) expression, but did not significantly affect neprilysin (NEP) and insulin-degrading enzyme (IDE) expression. Our data indicate that TPPB could direct APP processing towards the non-amyloidogenic pathway by increasing alpha-secretase activity, and suggest its therapeutic potential in AD.
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PMID:New protein kinase C activator regulates amyloid precursor protein processing in vitro by increasing alpha-secretase activity. 1765 Jan 13

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

The amyloid peptide (Abeta) deposited in Alzheimer's disease (AD) is generated by beta- and gamma-secretase processing of a larger integral membrane protein precursor (APP). Intramembrane processing of APP by gamma-secretase also yields an intracellular fragment, CTFgamma (a.k.a. AICD), which is highly conserved and is believed to regulate the transcription of several genes including KAI-1 and GSK3beta. The intracellular domain of APP is also processed by caspase to a 31 aa fragment that was shown to induce apoptosis by several groups. Although large quantities of CTFgamma are generated continuously by neurons, little if any is normally detected in cell lysates, which suggests that it is very rapidly turned over in vivo. Previous studies demonstrated that insulysin (IDE), an Abeta-degrading enzyme, is responsible for cytosol-mediated CTFgamma degradation in vitro. Consistent with this finding, knockout mice lacking IDE accumulate CTFgamma to detectable levels in the brain, although its levels remain lower than its precursor, suggesting that it continues to be turned over in the brain. Moreover, when we treated cultured cells with IDE inhibitors, we did not observe an increase in CTFgamma in cell lysates, suggesting that pathways other than IDE are also involved in CTFgamma turnover. To understand CTFgamma turnover further, we have mapped the IDE cleavage sites with the intention of mutating them to examine alternative pathways in future studies. Edman degradation revealed that IDE cleaves CTFgamma at multiple sites to small peptides ranging from 5 to 14 aa. The cleavage sites do not reveal the existence of any sequence specificity for IDE cleavage. Understanding the turnover mechanisms of CTFgamma is critical to the understanding of the signaling function of APP mediated by this fragment. The current study presents the interesting specificity of CTFgamma turnover by IDE, which has been previously identified as the major degrading enzyme for Abeta as well as CTFgamma. In addition, the study provides evidence for the presence of alternative CTFgamma-degrading pathways in the cell.
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PMID:Insulysin cleaves the APP cytoplasmic fragment at multiple sites. 1770 50

Compelling evidence indicates that excess consumption of sugar-sweetened beverages plays an important role in the epidemic of obesity, a major risk factor for type 2 diabetes mellitus. Type 2 diabetes mellitus has been associated with a higher incidence of Alzheimer disease (AD). High fat diets promote AD-like pathology in mice. It is not known whether consumption of excess sugar as in calorically sweetened beverages with an otherwise normal diet affects the development of AD. In the present study, we provided 10% sucrose-sweetened water to a transgenic mouse model of AD with a normal rodent diet. Compared with the control mice with no sucrose added in the water, the sucrose group gained more body weight and developed glucose intolerance, hyperinsulinemia, and hypercholesterolemia. These metabolic changes were associated with the exacerbation of memory impairment and a 2-3-fold increase in insoluble amyloid-beta protein levels and deposition in the brain. We further showed that the levels of expression and secretase-cleaved products of amyloid-beta precursor protein were not affected by sucrose intake. The steady-state levels of insulin-degrading enzyme did not change significantly, whereas there was a 2.5-fold increase in brain apoE levels. Therefore, we concluded that the up-regulation of apoE accelerated the aggregation of Abeta, resulting in the exacerbation of cerebral amyloidosis in sucrose-treated mice. These data underscore the potential role of dietary sugar in the pathogenesis of AD and suggest that controlling the consumption of sugar-sweetened beverages may be an effective way to curtail the risk of developing AD.
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PMID:Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. 1794 1

Fibrillar amyloid-beta protein (fAbeta) is the principal component of amyloid plaques in the brains of patients with Alzheimer's disease (AD). We have recently reported that activity of trypsin is inhibited by fAbeta and that trypsin can bind to fAbeta. Neprilysin and insulysin are important proteases for the clearance of soluble Abeta. Here, we report that fAbeta also binds to neprilysin and insulysin, which results in the inhibition of their proteolytic activities. These findings suggest that clearance of soluble Abeta may be defective in AD because of binding of proteases to amyloid plaques, leading to inactivation of proteases that are required for catabolism of Abeta. The identification of compounds that can inhibit binding of proteases to fAbeta may, therefore, be of significance for therapeutic intervention in AD. Congo red and Thioflavin T are widely used for histopathological examination of amyloid plaques because of their strong affinity to fibrillar amyloid proteins. We examined the effect of Congo red and Thioflavin T (potent fAbeta-binding compounds) on the binding of different proteases to fAbeta. While Congo red inhibited the binding of trypsin, neprilysin and insulysin to fAbeta, Thioflavin T did not have any effect. The effect of Congo red was concentration-dependent and the inhibitory effect was in the order of trypsin > insulysin > neprilysin. When the effect of prebound-Congo red to fAbeta was examined, trypsin was unable to bind to this complex suggesting that Congo red may have better affinity than trypsin for binding to fAbeta. Based on these results, we propose that the inhibition of binding of proteases to amyloid plaques may help in reducing the deposition of Abeta in AD.
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PMID:Binding of proteases to fibrillar amyloid-beta protein and its inhibition by Congo red. 1805 60

A cDNA encoding insulin-degrading enzyme (IDE) was cloned from tomato (Solanum lycopersicum) and expressed in Escherichia coli in N-terminal fusion with glutathione S-transferase. GST-SlIDE was characterized as a neutral thiol-dependent metallopeptidase with insulinase activity: the recombinant enzyme cleaved the oxidized insulin B chain at eight peptide bonds, six of which are also targets of human IDE. Despite a certain preference for proline in the vicinity of the cleavage site, synthetic peptides were cleaved at apparently stochastic positions indicating that SlIDE, similar to IDEs from other organisms, does not recognize any particular amino acid motif in the primary structure of its substrates. Under steady-state conditions, an apparent K(m) of 62+/-7 microm and a catalytic efficiency (k(cat)/K(m)) of 62+/-15 mm(-1) s(-1) were determined for Abz-SKRDPPKMQTDLY(NO(3))-NH(2) as the substrate. GST-SlIDE was effectively inhibited by ATP at physiological concentrations, suggesting regulation of its activity in response to the energy status of the cell. While mammalian and plant IDEs share many of their biochemical properties, this similarity does not extend to their function in vivo, because insulin and the beta-amyloid peptide, well-established substrates of mammalian IDEs, as well as insulin-related signaling appear to be absent from plant systems.
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PMID:Cloning, expression and characterization of insulin-degrading enzyme from tomato (Solanum lycopersicum). 1809 74

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

The accumulation of the amyloid beta-protein (Abeta), the main constituent of the 'amyloid plaque', is widely considered to be the key pathological event in Alzheimer's disease (AD). In particular, the accumulation of Abeta42 is the central event triggering neurodegeneration. Reduction of Abeta is now a major therapeutic strategy. However, only a few patients show evidence of increased Abeta production. Thus, defects in proteases that degrade Abeta could underlie some or many cases of familial and sporadic AD. Among the Abeta degrading enzymes, namely, neprilysin (NEP), insulin-degrading enzyme (IDE), endothelin-converting enzyme (ECE) and angiotensin-converting enzyme (ACE), ACE is the most commonly targeted enzyme by inhibitors in elderly populations because it plays a central role in the regulation of blood pressure and hypertension. Genetic, pathological and biochemical studies have associated ACE with AD. This review discusses genetic, molecular and clinical studies that might help explain the relationship between ACE, hypertension, Abeta degradation and AD.
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PMID:Angiotensin-converting enzyme as a potential target for treatment of Alzheimer's disease: inhibition or activation? 1914 83

In this study, we examined whether ischemia-induced amyloidogenesis could be modulated by environmental "experience," and whether this modulation is associated with improved cognitive functioning. Rats were subjected to either global ischemia or sham surgery and then were randomly assigned to either enriched environment housing (EE) or socially paired housing (controls). After 14 days of differential environmental housing, the rats were tested in the water maze. Our results show decreased C-terminal fragments of the beta-amyloid precursor protein (betaAPP) and decreased amyloid beta (Abeta) load in the ischemic EE rats compared to the ischemic control animals. In addition, Abeta oligomerization was significantly decreased in the ischemic EE animals compared to the ischemic control rats. Further, significantly increased levels of neprilysin, but not insulin-degrading enzyme, amyloid-degrading enzymes, were seen in the ischemic EE rats compared to the ischemic control animals. Behavioral analyses showed that ischemic EE rats performed significantly better on the memory task compared to the ischemic control group. These results suggest that use of multi-sensory environmental enrichment following cerebral ischemia may reduce the accumulation of Abeta peptide in the more pathologic oligomeric form, and consequently may enhance functional recovery.
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PMID:Environmental experience modulates ischemia-induced amyloidogenesis and enhances functional recovery. 2773 69

Accumulation of amyloid beta (Abeta) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of Abeta. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied Abeta oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to Abeta aggregation and subsequent synaptic loss.
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PMID:Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric a{beta}. 1940 47


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