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

Recently, a relationship between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the beta-amyloid precursor protein (betaAPP) in relationship with the pathogenesis of Alzheimer's disease (AD) has been suggested. Therefore, we studied the specific activity of GAPDH in the different animal models of AD: transgenic mice (Tg2576) and rats treated with beta-amyloid, or thiorphan, or lipopolysaccharides (LPS) and interferon gamma (INFgamma). We observed that GAPDH activity was significantly decreased in the brain samples from TG mice. The injection of beta-amyloid, or thiorphan, an inhibitor of neprilysin involved in beta-amyloid catabolism, in rat brains resulted in a pronounced reduction of the enzyme activity. The infusion of LPS and IFNgamma, which can influence the progression of the AD, significantly reduced the enzyme activity.
 ...
PMID:Decrease of dehydrogenase activity of cerebral glyceraldehyde-3-phosphate dehydrogenase in different animal models of Alzheimer's disease. 1732 18

Pathogenesis of Alzheimer's disease (AD), which is characterised by accumulation of extracellular deposits of beta-amyloid peptide (Abeta) in the brain, has recently been linked to vascular disorders such as ischemia and stroke. Abeta is constantly produced in the brain from amyloid precursor protein (APP) through its cleavage by beta- and gamma-secretases and certain Abeta species are toxic for neurones. The brain has an endogenous mechanism of Abeta removal via proteolytic degradation and the zinc metalloproteinase neprilysin (NEP) is a critical regulator of Abeta concentration. Down-regulation of NEP could predispose to AD. By comparing the effects of hypoxia and oxidative stress on expression and activity of the Abeta-degrading enzyme NEP in human neuroblastoma NB7 cells and rat primary cortical neurones we have demonstrated that hypoxia reduced NEP expression at the protein and mRNA levels as well as its activity. On contrary in astrocytes hypoxia increased NEP mRNA expression.
 ...
PMID:Effects of hypoxia and oxidative stress on expression of neprilysin in human neuroblastoma cells and rat cortical neurones and astrocytes. 1748 46

Cerebral deposition of the amyloid beta protein (Abeta), an invariant feature of Alzheimer's disease, reflects an imbalance between the rates of Abeta production and clearance. The causes of Abeta elevation in the common late-onset form of Alzheimer's disease (LOAD) are largely unknown. There is evidence that the Abeta-degrading protease neprilysin (NEP) is down-regulated in normal aging and LOAD. We asked whether a decrease in endogenous NEP levels can prolong the half-life of Abeta in vivo and promote development of the classic amyloid neuropathology of Alzheimer's disease. We examined the brains and plasma of young and old mice expressing relatively low levels of human amyloid precursor protein and having one or both NEP genes silenced. NEP loss of function 1) elevated whole-brain and plasma levels of human Abeta(40) and Abeta(42), 2) prolonged the half-life of soluble Abeta in brain interstitial fluid of awake animals, 3) raised the concentration of Abeta dimers, 4) markedly increased hippocampal amyloid plaque burden, and 5) led to the development of amyloid angiopathy. A approximately 50% reduction in NEP levels, similar to that reported in some LOAD brains, was sufficient to increase amyloid neuropathology. These findings demonstrate an important role for proteolysis in determining the levels of Abeta and Abeta-associated neuropathology in vivo and support the hypothesis that primary defects in Abeta clearance can cause or contribute to LOAD pathogenesis.
 ...
PMID:Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy. 1759 69

Amyloid-beta (Abeta) deposition is a major pathological hallmark of Alzheimer's disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower Abeta secretion, and it is considered a potential basis for novel therapies for Alzheimer's disease. Here, we show that Gleevec decreases Abeta levels without the inhibition of Notch cleavage by a mechanism distinct from gamma-secretase inhibition. Gleevec does not influence gamma-secretase activity in vitro; however, treatment of cell lines leads to a dose-dependent increase in the amyloid precursor protein intracellular domain (AICD), whereas secreted Abeta is decreased. This effect is observed even in presence of a potent gamma-secretase inhibitor, suggesting that Gleevec does not activate AICD generation but instead may slow down AICD turnover. Concomitant with the increase in AICD, Gleevec leads to elevated mRNA and protein levels of the Abeta-degrading enzyme neprilysin, a potential target gene of AICD-regulated transcription. Thus, the Gleevec mediated-increase in neprilysin expression may involve enhanced AICD signaling. The finding that Gleevec elevates neprilysin levels suggests that its Abeta-lowering effect may be caused by increased Abeta-degradation.
 ...
PMID:Gleevec increases levels of the amyloid precursor protein intracellular domain and of the amyloid-beta degrading enzyme neprilysin. 1762 63

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.
 ...
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.
 ...
PMID:New insights into the roles of metalloproteinases in neurodegeneration and neuroprotection. 1767 58

Considerable progress has been made in recent years towards better understanding the pathogenesis of Alzheimer's disease (AD), a dementing neurodegenerative disorder that affects > 10 million individuals in the US and Europe combined. Recent studies suggest that alterations in the processing of amyloid precursor protein (APP), resulting in the accumulation of amyloid-beta protein (Abeta) and the formation of oligomers leads to synaptic damage and neurodegeneration. Therefore, strategies for treatment development have been focused on reducing Abeta accumulation using, among other approaches, antiaggregation molecules, regulators of the APP proteolysis and processing, reducing APP production (e.g., small-interfering RNA), and increasing Abeta clearance with antibodies, apolipoprotein E and Abeta-degrading enzymes (e.g., neprilysin). The main focus of this review is on novel treatments for AD with a special emphasis on delivering neuroprotective and antiamyloidogenic molecules by gene therapy and by promoting neurogenesis.
 ...
PMID:Novel strategies for Alzheimer's disease treatment. 1803 51

Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of Abeta peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Abeta peptide, similar but not identical to the Abeta peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Abeta, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Abeta 42 levels, except for the Arctic mutation, which alters the Abeta sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Abeta deposition in most mouse lines. Doubly (APP x mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of Abeta. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Abeta in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in Abeta oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau -/- background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of Abeta or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis.
 ...
PMID:Alzheimer disease models and human neuropathology: similarities and differences. 1803 75

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.
 ...
PMID:Binding of proteases to fibrillar amyloid-beta protein and its inhibition by Congo red. 1805 60

Cerebral amyloid angiopathy (CAA) of the amyloid-beta (Abeta) type is the most common form of sporadic CAA and is now also accepted as an early and integral part of Alzheimer's disease (AD) pathogenesis. Cerebral amyloid angiopathy is a risk factor for haemorrhagic stroke and is believed to independently contribute to dementia. Rare forms of hereditary cerebral amyloidosis caused by mutations within the Abeta domain of amyloid precursor protein (APP) have been identified, where mutant Abeta preferably deposits in vessels because of a decreased fibrillogenic potential and/or increased vasotopicity. A review of factors involved in CAA caused by wild-type Abeta suggests that increased Abeta levels in brain without an increased Abeta42/Abeta40 ratio is one of the most important prerequisites for vascular amyloidosis. This is exemplified by CAA observed in APP duplication and Down's syndrome patients, neprilysin polymorphism patients and knockout mice and Swedish APP (KM670/671NL) mice. Select presenilin mutations also lead to a prominent CAA, and importantly, presenilin mutations are shown to have varied effects on the production of Abeta40, the predominant amyloid found in CAA. Conversely, APP mutations such as Austrian APP (T714I) drastically decrease Abeta40 production and are deficient in CAA. Apolipoprotein E-epsilon4 is also shown to be a risk factor for CAA, and this might be because of its specific role in the aggregation of Abeta40. Recent data also suggest that dense-core senile plaques in humans and dense plaques in transgenic mice, composed predominantly of Abeta40, associate with vessels. This review highlights some of these aspects of genetics and biochemistry of CAA and pathological descriptions linked to a prominent CAA and/or dense plaques in humans and relevant mouse models and discusses how this knowledge has led to a better understanding of the processes involved in vascular amyloidosis, and in causing dementia, and thus has important therapeutic implications.
 ...
PMID:Cerebral amyloid angiopathy: pathogenetic mechanisms and link to dense amyloid plaques. 1818 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>