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)

Microglia accumulation at the site of amyloid plaques is a strong indication that microglia play a major role in Alzheimer's disease pathogenesis. However, how microglia affect amyloid-beta peptide (Abeta) deposition remains poorly understood. To address this question, we developed a novel bigenic mouse that overexpresses both amyloid precursor protein (APP) and monocyte chemotactic protein-1 (MCP-1; CCL2 in systematic nomenclature). CCL2 expression, driven by the glial fibrillary acidic protein promoter, induced mononuclear phagocyte (MP; monocyte-derived macrophage and microglial) accumulation in the brain. When APP/CCL2 transgenic mice were compared to APP mice, a fivefold increase in Abeta deposition was present despite increased MP accumulation around hippocampal and cortical amyloid plaques. Levels of full-length APP, its C-terminal fragment, and Abeta-degrading enzymes (insulin-degrading enzyme and neprilysin) in APP/CCL2 and APP mice were indistinguishable. Sodium dodecyl sulfate-insoluble Abeta (an indicator of fibrillar Abeta) was increased in APP/CCL2 mice at 5 months of age. Apolipoprotein E, which enhances Abeta deposition, was also increased (2.2-fold) in aged APP/CCL2 as compared to APP mice. We propose that although CCL2 stimulates MP accumulation, it increases Abeta deposition by reducing Abeta clearance through increased apolipoprotein E expression. Understanding the mechanisms underlying these events could be used to modulate microglial function in Alzheimer's disease and positively affect disease outcomes.
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PMID:Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition. 1585 47

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-beta (Abeta) plaques in the frontal cortex (38%; p = 0.018), the cortex at the level of the hippocampus (53%; p = 0.0003), and the hippocampus (40%; p = 0.06). This was associated with decreased cortical Abeta1-40 (35%; p = 0.005) and Abeta1-42 (22%; p = 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [for alpha-C-terminal fragment (alpha-CTF), 54% and p = 0.04; for beta-CTF, 35% and p = 0.03]. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant (p < 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.
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PMID:Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. 1585 47

Neprilysin has been reported to be a major beta-amyloid peptide (Abeta)-degrading enzyme. The decreased expression and activity of it may contribute to the development of Alzheimer's disease by promoting the accumulation of Abeta. We used denaturing high-performance liquid chromatography to screen the neprilysin gene (NEP) for single nucleotide polymorphisms (SNPs) in 257 Chinese sporadic Alzheimer's disease patients and 242 cognitive normal controls. As a result, eight novel and one known SNP were identified. Three of them, -204G-->C in the promoter region, IVS17-294C-->T, and IVS22+36C-->A showed a significant association with Alzheimer's disease (p = .006,.017, and.003, respectively). Subsequent haplotype analysis provided further evidence of the association (global p < .0001 for the three SNPs mentioned above, and global p < .01 for the eight SNPs with rare allele frequency > 1%). These findings indicate that genetic variations within or extremely close to NEP might influence the susceptibility to Alzheimer's disease in Chinese persons.
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PMID:Mutation screening and association study of the neprilysin gene in sporadic Alzheimer's disease in Chinese persons. 1586 Apr 64

Amyloid beta-peptide (Abeta), which plays a central role in Alzheimer's disease, is generated by presenilin-dependent gamma-secretase cleavage of beta-amyloid precursor protein (betaAPP). We report that the presenilins (PS1 and PS2) also regulate Abeta degradation. Presenilin-deficient cells fail to degrade Abeta and have drastic reductions in the transcription, expression, and activity of neprilysin, a key Abeta-degrading enzyme. Neprilysin activity and expression are also lowered by gamma-secretase inhibitors and by PS1/PS2 deficiency in mouse brain. Neprilysin activity is restored by transient expression of PS1 or PS2 and by expression of the amyloid intracellular domain (AICD), which is cogenerated with Abeta, during gamma-secretase cleavage of betaAPP. Neprilysin gene promoters are transactivated by AICDs from APP-like proteins (APP, APLP1, and APLP2), but not by Abeta or by the gamma-secretase cleavage products of Notch, N- or E- cadherins. The presenilin-dependent regulation of neprilysin, mediated by AICDs, provides a physiological means to modulate Abeta levels with varying levels of gamma-secretase activity.
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PMID:Presenilin-dependent transcriptional control of the Abeta-degrading enzyme neprilysin by intracellular domains of betaAPP and APLP. 1729 50

This study reveals that the chick embryo has active the machinery for the production and degradation of the amyloid beta peptide characteristic of Alzheimer's disease. We cloned the principal beta-amyloid precursor protein isoforms in the chick embryo and observed that they are highly homologous to the human sequences and identical at the C-terminal sequence, including the amyloid beta domain. Mammals such as rat or mouse, more commonly used as animal models of human diseases, have a distinct amyloid beta sequence. The distribution of beta-amyloid precursor protein isoforms in the chick embryo revealed that, as in humans, their expression is ubiquitous and the prototype beta-amyloid precursor protein-695 predominated in the nervous system. We also found that the chick embryo expresses the genes for the main proteolytic proteases implicated in the production of amyloid beta, including BACE-1, BACE-2, presenilin-1, presenilin-2 and nicastrin, as well as the amyloid beta-degrading enzyme neprilysin, or ADAM-17, a protease implicated in the non-amyloidogenic processing of beta-amyloid precursor protein. We have also found that between amyloid beta40 and amyloid beta42, this latter seems to be the major amyloid beta peptide produced during chick embryogenesis. The chick embryo appears as a suitable natural model to study cell biology and developmental function of beta-amyloid precursor protein and a potential assay system for drugs that regulate beta-amyloid precursor protein processing.
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PMID:The chick embryo appears as a natural model for research in beta-amyloid precursor protein processing. 1603 87

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

Accumulation of insoluble aggregates of amyloid-beta peptide (Abeta), a cleavage product of amyloid precursor protein (APP), is thought to be central to the pathogenesis of Alzheimer's disease (AD). Consequently, downregulation of APP, or enhanced clearance of Abeta, represent possible therapeutic strategies for AD. We generated replication-defective herpes simplex virus (HSV) vectors that inhibit Abeta accumulation, both in vitro and in vivo. In cell culture, HSV vectors expressing either (i) short hairpin RNA directed to the APP transcript (HSV-APP/shRNA), or (ii) neprilysin, an endopeptidase that degrades Abeta (HSV-neprilysin), substantially inhibited accumulation of Abeta. To determine whether these vectors showed similar activity in vivo, we developed a novel mouse model, in which overexpression of a mutant form of APP in the hippocampus, using a lentiviral vector (LV-APP(Sw)), resulted in rapid Abeta accumulation. Co-inoculation of LV-APP(Sw) with each of the HSV vectors showed that either HSV-APP/shRNA or HSV-neprilysin inhibited Abeta accumulation in this model, whereas an HSV control vector did not. These studies demonstrate the utility of HSV vectors for reducing Abeta accumulation in the brain, thus providing useful tools to clarify the role of Abeta in AD that may facilitate the development of novel therapies for this important disease.
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PMID:Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-beta peptide in vivo. 1654 Nov 22

Early pathogenic events in Alzheimer's disease (AD) involve increased production and/or reduced clearance of beta-amyloid (Abeta), especially the 42 amino acid fragment Abeta1-42. The Abeta1-42 peptide is generated through cleavage of the amyloid precursor protein by beta- and gamma-secretase and is catabolised by a variety of proteolytic enzymes such as insulin-degrading enzyme and neprilysin. Here, we describe a method that employs immunoprecipitation combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to determine the pattern of C-terminally truncated Abeta peptides in cerebrospinal fluid (CSF). Using antibodies coupled to magnetic beads, we have detected 18 C-terminally and 2 N-terminally truncated Abeta peptides in CSF. By determining the identity and profile of the truncated Abeta peptides, more insight may be gained about differences in the metabolism and structural properties of Abeta in AD. Finally, the Abeta fragment signatures may prove useful as a diagnostic test for AD.
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PMID:Determination of beta-amyloid peptide signatures in cerebrospinal fluid using immunoprecipitation-mass spectrometry. 1660 10

The amyloidogenesis occurring in Alzheimer's disease represents a fundamental membrane-related pathology involving a membrane-bound substrate metabolized by integral membrane proteases (secretases). Thus, the amyloid-beta peptide (Abeta), which accumulates extracellularly as plaques in the brains of Alzheimer's disease patients, is derived by sequential proteolytic cleavage of the integral transmembrane amyloid precursor protein (APP). Beta-Secretase or BACE-1 (beta-site APP cleaving enzyme) is a transmembrane aspartic protease responsible for the first of these cleavage events, generating the soluble APP ectodomain sAPPbeta, and a C-terminal fragment CTFbeta. CTFbeta is subsequently cleaved by the ?gamma-secretase complex, of which presenilin is the catalytic core, to produce Ass. A variety of studies indicate that cholesterol is an important factor in the regulation of Ass production, with high cholesterol levels being linked to increased Ass generation and deposition. However, the mechanism(s) underlying this effect are unclear at present. Recent evidence suggests that amyloidogenic APP processing may preferentially occur in the cholesterol-rich regions of membranes known as lipid rafts, and that changes in cholesterol levels could exert their effects by altering the distribution of APP-cleaving enzymes within the membrane. Rafts may be involved in the aggregation of Ass and also in its clearance by amyloid-degrading enzymes such as plasmin or possibly neprilysin (NEP).
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PMID:The involvement of lipid rafts in Alzheimer's disease. 1661 86

A subtle but chronic alteration in metabolic balance between amyloid-beta peptide (Abeta) anabolic and catabolic activities is thought to cause Abeta accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of Abeta in the brain causes neuronal dysfunction in vivo. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred amyloid precursor protein (APP) transgenic mice (APP23) with neprilysin-deficient mice and biochemically and immunoelectron-microscopically analyzed Abeta accumulation in the brain. We also examined hippocampal synaptic plasticity using an in vivo recording technique and cognitive function using a battery of learning and memory behavior tests, including Y-maze, novel-object recognition, Morris water maze, and contextual fear conditioning tests at the age of 13-16 weeks. We present direct experimental evidence that reduced activity of neprilysin, the major Abeta-degrading enzyme, in the brain elevates oligomeric forms of Abeta at the synapses and leads to impaired hippocampal synaptic plasticity and cognitive function before the appearance of amyloid plaque load. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of Alzheimer disease. This supports the idea that a strategy to reduce Abeta oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms.
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PMID:Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function. 1663 59


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