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)

Deposition of plaques containing amyloid beta (Abeta) peptides is a neuropathological hallmark of Alzheimer's disease (AD). Here we demonstrate that neuronal overexpression of the epsilon isozyme of PKC decreases Abeta 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, APP/PKCepsilon doubly transgenic mice had decreased Abeta levels but showed no evidence for altered cleavage of APP. Instead, PKCepsilon overexpression selectively increased the activity of endothelin-converting enzyme, which degrades Abeta. The activities of other Abeta-degrading enzymes, insulin degrading enzyme and neprilysin, were unchanged. These results indicate that increased neuronal PKCepsilon activity can promote Abeta clearance and reduce AD neuropathology through increased endothelin-converting enzyme activity.
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PMID:PKCepsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice. 1670 31

The pathological hallmark of Alzheimer disease is the senile plaque principally composed of tightly aggregated amyloid-beta fibrils (fAbeta), which are thought to be resistant to degradation and clearance. In this study, we explored whether proteases capable of degrading soluble Abeta (sAbeta) could degrade fAbeta as well. We demonstrate that matrix metalloproteinase-9 (MMP-9) can degrade fAbeta and that this ability is not shared by other sAbeta-degrading enzymes examined, including endothelin-converting enzyme, insulin-degrading enzyme, and neprilysin. fAbeta was decreased in samples incubated with MMP-9 compared with other proteases, assessed using thioflavin-T. Furthermore, fAbeta breakdown with MMP-9 but not with other proteases was demonstrated by transmission electron microscopy. Proteolytic digests of purified fAbeta were analyzed with matrix-assisted laser desorption ionization time-of-flight mass spectrometry to identify sites of Abeta that are cleaved during its degradation. Only MMP-9 digests contained fragments (Abeta(1-20) and Abeta(1-30)) from fAbeta(1-42) substrate; the corresponding cleavage sites are thought to be important for beta-pleated sheet formation. To determine whether MMP-9 can degrade plaques formed in vivo, fresh brain slices from aged APP/PS1 mice were incubated with proteases. MMP-9 digestion resulted in a decrease in thioflavin-S (ThS) staining. Consistent with a role for endogenous MMP-9 in this process in vivo, MMP-9 immunoreactivity was detected in astrocytes surrounding amyloid plaques in the brains of aged APP/PS1 and APPsw mice, and increased MMP activity was selectively observed in compact ThS-positive plaques. These findings suggest that MMP-9 can degrade fAbeta and may contribute to ongoing clearance of plaques from amyloid-laden brains.
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PMID:Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. 1678 29

Deposition of amyloid beta-protein (Abeta) in the brain is an early and invariant neuropathological feature of Alzheimer's disease (AD). The current search for anti-AD drugs is mainly focused on modification of the process of accumulation of Abeta in the brain. Here, we review four anti-amyloidogenic strategies: (i) reduction of Abeta production, which has mainly been approached with secretase inhibition, (ii) promotion of the Abeta degrading catabolic pathway, including an Abeta degrading enzyme, neprilysin, (iii) immunotherapy for Abeta and (iv) inhibition of Abeta aggregation. We have reported that AD patients have a favorable molecular environment for Abeta aggregation and that various compounds, such as polyphenols, interfere with Abeta aggregation and destabilize preformed Abeta fibrils.
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PMID:Anti-amyloidogenic therapies: strategies for prevention and treatment of Alzheimer's disease. 1680 37

Alzheimer's disease is recognized post mortem by the presence of extracellular senile plaques, made primarily of aggregation of amyloid beta peptide (Abeta). This peptide has consequently been regarded as the principal toxic factor in the neurodegeneration of Alzheimer's disease. As such, intense research effort has been directed at determining its source, activity and fate, primarily with a view to preventing its formation or its biological activity, or promoting its degradation. Clearly, much progress has been made concerning its formation by proteolytic processing of the amyloid precursor protein, and its degradation by enzymes such as neprilysin and insulin degrading enzyme. The activities of Abeta, however, are numerous and yet to be fully elucidated. What is currently emerging from such studies is a diffuse but steadily growing body of data that suggests Abeta has important physiological functions and, further, that it should only be regarded as toxic when its production and degradation are imbalanced. Here, we review these data and suggest that physiological levels of Abeta have important physiological roles, and may even be crucial for neuronal cell survival. Thus, the view of Abeta being a purely toxic peptide requires re-evaluation.
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PMID:Physiological roles for amyloid beta peptides. 1680 72

Loss of Locus coeruleus (LC) noradrenergic (NA) neurons occurs in several neurodegenerative conditions including Alzheimer's disease (AD). In vitro and in vivo studies have shown that NA influences several features of AD disease including inflammation, neurodegeneration, and cognitive function. In the current study we tested if LC loss influenced beta amyloid (Abeta) plaque deposition. LC neuronal degeneration was induced in transgenic mice expressing mutant V717F human amyloid precursor protein (APP) by treatment with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine DSP4 (5mg/kg every 2 weeks beginning at age 3 months). At 9 months of age, when control mice show low amyloid load, DSP4-treated mice showed an approximately 5-fold increase in the average number of Abeta plaques. This was accompanied by an increase in the levels of APP C-terminal cleavage fragments. DSP4-treatment increased both microglial and astroglial activation. In vivo, DSP4-treatment decreased expression and activity of the Abeta degrading enzyme neprilysin, while in vitro NA increased phagocytosis of Abeta1-42 by microglia. These findings suggest that noradrenergic innervation from LC are needed to maintain adequate Abeta clearance, and therefore that LC degeneration could contribute to AD pathogenesis.
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PMID:Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease. 1683 4

Accumulation of the beta-amyloid peptide (Abeta) in the brain is a major pathological hallmark of Alzheimer's disease (AD), leading to synaptic dysfunction, neuronal death, and memory impairment. The levels of neprilysin, a major Abeta-degrading enzyme, are decreased in AD brains and during aging. Because neprilysin cleaves Abeta in vivo, its down-regulation may contribute to the pathophysiology of AD. The aim of this study was to assess the consequences of neprilysin deficiency on accumulation of murine Abeta in brains and associated pathologies in vivo by investigating neprilysin-deficient mice on biochemical, morphological, and behavioral levels. Aged neprilysin-deficient mice expressed physiological amyloid precursor protein (APP) levels and exhibited elevated brain Abeta concentrations and amyloid-like deposits in addition to signs of neuronal degeneration in their brains. Behaviorally, neprilysin-deficient mice acquired a significantly weaker conditioned taste aversion that extinguished faster than the aversion of age-matched controls. Our data establish that, under physiological APP expression levels, neprilysin deficiency is associated with increased Abeta accumulation in the brain and leads to deposition of amyloid-like structures in vivo as well as with signs of AD-like pathology and with behavioral deficits.
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PMID:Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo. 1699 1

Converging evidence links abnormally high brain concentrations of amyloid-beta peptides (Abeta) to the pathology of Alzheimer's disease (AD). Lowering brain Abeta levels, therefore, is a therapeutic strategy for the treatment of AD. Neuronal neprilysin upregulation led to increased degradation of Abeta, reduced the formation of Abeta-plaques and the associated cytopathology, but whether overexpression of neprilysin can improve cognition is unknown. We show that neuronal overexpression of neprilysin improved the Morris water maze memory performance in mice with memory deficits resulting from overexpression of the AD-causing mutated human amyloid precursor protein (APP). This improvement was associated with decreased brain levels of Abeta and with unchanged endoproteolytic processing of APP. These results provide the evidence that lowering of brain Abeta levels by increasing its degradation can improve cognitive functions in vivo, and suggest that increasing the activity of neprilysin in brain may be effective in preventing cognitive decline in AD.
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PMID:Neuronal neprilysin overexpression is associated with attenuation of Abeta-related spatial memory deficit. 1700 8

Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the beta-secretase site. Apart from this cleavage, the functional importance of Bace1 in other physiological events is unknown. We show here that Bace1 regulates the process of myelination and myelin sheath thickness in the central and peripheral nerves. In Bace1-null mice, the process of myelination was delayed and myelin thickness was markedly reduced, indicating that genetic deletion of Bace1 causes hypomyelination. Bace1-null mice also showed altered neurological behaviors such as elevated pain sensitivity and reduced grip strength. Further mechanistic studies showed an altered neuregulin-Akt signaling pathway in Bace1-null mice. Full-length neuregulin-1 was increased and its cleavage product was decreased in the CNS of Bace1-null mice. Furthermore, phosphorylated Akt was also reduced. Based upon these and previous studies, we postulate that neuronally enriched Bace1 cleaves neuregulin-1 and that processed neuregulin-1 regulates myelination by means of phosphorylation of Akt in myelin-forming cells.
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PMID:Bace1 modulates myelination in the central and peripheral nervous system. 1709 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

One of the notable features of Alzheimer's disease (AD) is the overabundance of beta-amyloid peptides in brain fluids, leading to the formation and deposition of insoluble amyloid plaques. Previous work in this lab demonstrates that the normal choroid plexus, a primary component of the blood-cerebrospinal fluid barrier, has the capacity to remove beta-amyloid from the cerebrospinal fluid, potentially preventing the formation of beta-amyloid plaques. The purpose of this work was to determine whether the choroid plexus and/or the brain capillaries, a primary component of the blood-brain barrier, possessed the capacity to produce or degrade beta-amyloid peptides. Using quantitative real-time RT-PCR, immunodetection and enzyme activity assays, we demonstrated the presence in brain barriers of several key enzymes involved in beta-amyloid production, namely, amyloid precursor protein and beta-secretase, and in beta-amyloid metabolism and alternate processing, such as insulin degrading enzyme, endothelin-converting enzyme-1, neprilysin and alpha-secretase. Furthermore, beta-amyloid presence, in the absence of its application in culture media, was detected in an immortalized choroidal epithelial cell line, known as Z310 cells. The ability of the choroid plexus to produce and degrade beta-amyloid, in addition to its transport function, suggests a vital role of this tissue in maintaining beta-amyloid homeostasis. Disruption of this homeostasis due to aging, injury or toxicant exposure may contribute to accumulation of beta-amyloid peptides in the brain fluids, leading to AD.
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PMID:Macromolecules involved in production and metabolism of beta-amyloid at the brain barriers. 1727 14


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