Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormal deposition and accumulation of Alzheimer's amyloid beta-protein (A beta) and degeneration of forebrain cholinergic neurons are among the principal features of Alzheimer's disease. Studies in rat model systems have shown that forebrain cholinergic deficits are accompanied by induction of cortical beta-amyloid precursor protein (beta-APP) mRNAs and increased levels of secreted beta-APP in the CSF. The studies reported here determined whether the CSF levels of secreted beta-APP could be altered pharmacologically. In different experiments, rats with lesions of the forebrain cholinergic system received injections of vehicle, a muscarinic receptor antagonist scopolamine, or one of two cholinesterase inhibitors - diisopropyl phosphorofluoridate (DFP) or phenserine. Scopolamine was administered to determine whether the levels of beta-APP in the CSF could be increased by anticholinergic agents. The cholinesterase inhibitors were administered to determine whether the forebrain cholinergic system lesion-induced increases in CSF beta-APP could be reduced by cholinergic augmentation. Scopolamine administration led to a significant increase in the CSF levels of secreted beta-APP in sham-lesioned rats. Phenserine, a novel, reversible acetyl-selective cholinesterase inhibitor, significantly decreased the levels of secreted beta-APP in the CSF of forebrain cholinergic system-lesioned rats whereas DFP, a relatively non-specific cholinesterase inhibitor, failed to affect CSF levels of secreted beta-APP. These results suggest that the levels of secreted beta-APP in the CSF can be pharmacologically modulated but that this modulation is dependent upon the status of the forebrain cholinergic system and the pharmacological properties of the drugs used to influence it.
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PMID:Pharmacological modulation of Alzheimer's beta-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions. 919 Oct 90

One of the characteristic changes that occurs in Alzheimer's disease is the loss of acetylcholinesterase (AChE) from both cholinergic and noncholinergic neurons of the brain. However, AChE activity is increased around amyloid plaques. This increase in AChE may be of significance for therapeutic strategies using AChE inhibitors. The aim of this study was to examine the effect of amyloid beta-protein (A beta), the major component of amyloid plaques, on AChE expression. A beta peptides spanning residues 1-40 or 25-35 increased AChE activity in P19 embryonal carcinoma cells. A peptide containing a scrambled A beta(25-35) sequence did not stimulate AChE expression. To examine the possibility that the increase in AChE expression was mediated by an influx of calcium through voltage-dependent calcium channels (VDCCs), drugs acting on VDCCs were tested for their effects. Inhibitors of L-type VDCCs (diltiazem, nifedipine, and verapamil), but not N- or P- or Q-type VDCCs, resulted in a decrease in AChE expression. Agonists of L-type VDCCs (maitotoxin and S(-)-Bay K 8644) increased AChE expression. As L-type VDCCs are known to be modulated by cyclic AMP-dependent protein kinase, the effect of the adenylate cyclase activator forskolin was also examined. Forskolin stimulated AChE expression, an action that was blocked by the L-type VDCC antagonist nifedipine. The A beta(25-35)induced increase in AChE expression was mediated by an L-type VDCC, as the effect was also blocked by nifedipine. The results suggest that the increase in AChE expression around amyloid plaques could be due to a disturbance in calcium homeostasis involving the opening of L-type VDCCs.
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PMID:The amyloid beta-protein of Alzheimer's disease increases acetylcholinesterase expression by increasing intracellular calcium in embryonal carcinoma P19 cells. 928 41

One of the main characteristics of Alzheimer's disease (AD) is the cerebrovascular deposition of the amyloid beta-peptide (A beta), which is derived from a larger beta-amyloid precursor protein (beta APP). The majority of beta APP is processed by either a secretory of lysosomal/endosomal pathway. Carboxyl-truncated soluble derivatives of beta APP (sAPP) are generated by the proteolytic processing of full-length beta APP by either alpha- or beta-secretase enzyme. Our objective is to determine whether the processing of beta APP can be regulated by cholinesterase inhibitors, some of which were shown to produce a moderate improvement in memory and cognitive functions in patients with Alzheimer's disease. Here we have analyzed the levels of sAPP derivatives in cultured cells treated with different drugs by immunoblotting samples of conditioned media. The immunoreactive protein bands were developed by probing with the monoclonal antibody 22C11. Treating neuroblastoma, pheochromocytoma and fibroblast cells with high dose of either 3,4-diaminopyridine, metrifonate, or physostigmine did not inhibit the secretion of sAPP. Treating glioblastoma with either 3,4-diaminopyridine or metrifonate showed an increase in secretion of sAPP. However, treatment of cells with tacrine reduced release of sAPP in conditioned media of cell lines studied. The difference in action of metrifonate, physostigmine, and tacrine on beta APP is independent of their anticholinesterase activities. Our results suggests that noncatalytic functions of cholinesterase inhibitors can be utilized to alter the metabolism of beta APP, which might in turn affect the process of deposition of A beta, a key component of the cerebrovascular amyloid detected in AD.
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PMID:Effects of cholinesterase inhibitors on the secretion of beta-amyloid precursor protein in cell cultures. 932 15

The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid beta-peptide (A beta) derived from a larger beta-amyloid precursor protein (betaAPP). The majority of betaAPP is processed by either a secretory or lysosomal/endosomal pathway. Soluble derivatives of betaAPP (sAPP) and A beta generated by the proteolytic processing of full-length betaAPP are normally secreted into the conditioned medium of cultured cells. Tacrine, a centrally active potent cholinesterase inhibitor that has been shown to improve cognitive functions in some patients with AD, inhibits the secretion of sAPP. Here we have investigated whether leupeptin, a lysosomal protease inhibitor, could influence this effect of tacrine. We analyzed levels of betaAPP derivatives in cultured HeLa cells by immunoblotting cell lysates and conditioned media using the monoclonal antibody 22C11. Levels of sAPP normally present in conditioned media were severely reduced by treating cells with tacrine. The treatment of cells with tacrine resulted in a small decrease in the intracellular levels of betaAPP. The effect of treating the cells with tacrine did not depend upon the growing state of the cells as a similar effect was observed when the drug was added either during initial plating of the cells or after the attachment of the cells. The effect of tacrine was not affected by preincubating the cells with low serum in the culture medium. The treatment of cells with tacrine plus leupeptin reduced the secretion of sAPP in the medium to the same degree as did the treatment with tacrine alone, suggesting that the tacrine-mediated inhibition of sAPP release may not involve leupeptin-sensitive proteolytic pathways. The results suggest that the inhibitory effect of tacrine on sAPP secretion is not due to the proteolytic cleavage of the holoprotein in the medium.
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PMID:The effect of tacrine and leupeptin on the secretion of the beta-amyloid precursor protein in HeLa cells. 936 5

Alzheimer's disease (AD) is a common neurodegenerative disorder and a leading cause of death among the elderly. Recent advances in our understanding of the neurobiology of AD have provided scientific groundwork for the development of potentially more effective and less toxic treatment strategies for the disease. Some of the neuropathological hallmarks of AD include early and extensive degeneration of cortically projecting cholinergic neurons in the basal forebrain, and a reduced number of muscarinic acetylcholine receptors. Of note, neocortical muscarinic receptors of the M1 subtype are relatively preserved in the brains of patients with AD, whereas the presynaptic receptors, which are of the M2 subtype, are reduced in number. Therefore, activation of relatively intact postsynaptic mechanisms by muscarinic M1 receptor-specific agonists could theoretically be more efficacious in the treatment of AD compared with agents (e.g. acetylcholinesterase inhibitors) that predominantly act on dysfunctional presynaptic terminals. The administration of muscarinic agonists can demonstrably enhance cognition and significantly improve some of the disturbing behaviours in patients with AD. Recent advances in our knowledge of the molecular biology of muscarinic receptors, together with a better understanding of signal transduction pathways in AD, are likely to result in the development of receptor-specific muscarinic agonists that are more efficacious and less toxic. Moreover, preliminary evidence concerning the effects of muscarinic agonists on the processing of amyloid precursor protein and the formation of neurofibrillary tangles suggests that these agents might favourably alter the pathobiology of AD.
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PMID:Potential role of muscarinic agonists in Alzheimer's disease. 941 2

It has been suggested that acetylcholinesterase (AChE) has both a putative proteolytic activity against the amyloid precursor protein (APP), and a capacity to accelerate the assembly of amyloid-beta-peptide (Abeta) into Alzheimer's fibrils. Here, we have studied the ability of bovine brain AChE to share both activities. Results indicate that AChE purified through acridinium was able to process the APP peptides, however after further purification by an edrophonium column, the protease activity was lost. Under both conditions the capacity of the enzyme to promote amyloid formation was maintained. Kinetic studies of the Abeta aggregation process using edrophonium-AChE, indicated that the lag phase of the aggregation process was smaller than the one observed with the esterase purified by acridinium alone. Considering that the total amount of amyloid formed, measured by thioflavine-T fluorescence, was similar for both AChE preparations, our results suggest that the edrophonium-AChE possesses an higher intrinsic capacity to stimulate the aggregation of Abeta(1-40) peptide.
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PMID:Brain acetylcholinesterase promotes amyloid-beta-peptide aggregation but does not hydrolyze amyloid precursor protein peptides. 947 6

Alzheimer's disease (AD) is the most common neurodegenerative disorder that causes cognitive deficits in the elderly. Its neuropathology is characterized by amyloid deposition and specific cholinergic degeneration. To address the link between amyloid formation and cholinergic loss, we examined histologically the amyloid precursor protein (APP) changes following selective immunolesion of the basal forebrain cholinergic system with 192 IgG-saporin in rats at 6 months post-lesion. In such rats with cognitive deficits observed in Morris water maze tests, we found increased levels of APP by optical density measurements in regions of cholinergic denervation. APP elevation and performance in the water maze task correlate with reduction of acetyl-cholinesterase (AChE) activity in the frontal cortex and CA3 subfield of hippocampus. The data indicate that loss of cholinergic innervation can affect APP expression.
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PMID:Chronic cognitive deficits and amyloid precursor protein elevation after selective immunotoxin lesions of the basal forebrain cholinergic system. 951 4

Metrifonate is a cholinesterase inhibitor with a long-lasting inhibition that raises brain acetylcholine levels. It is well-absorbed and has limited binding to serum proteins. In preliminary studies of its utility in the treatment of Alzheimer disease's (AD), it led to improvements of cognition or reduced the rate of decline of cognition compared with placebo. It also benefited the global function of these patients. Side effects include nausea, cramping, and diarrhea. Metrifonate has promise as a well-tolerated treatment of the symptoms of AD.
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PMID:Metrifonate: overview of safety and efficacy. 954 64

Long-term behavioral effects, changes in learning and memory functions and aberrations of cholinergic fibers projecting to the parietal cortex were investigated after bilateral injections of beta-amyloid(Phe(SO3H)24)25-35 peptide in rat nucleus basalis magnocellularis (nbm). The beta-amyloid peptide used in these experiments contained the original beta-amyloid 25-35 sequence which was coupled to a phenylalanine-sulphonate group at position 24. This additional residue serves as a protective cap on the molecule without influencing its neurotoxic properties and results in water-solubility, stability and low rates of peptide metabolism. In this paper, home cage, locomotor and open-field activities, passive shock-avoidance and 'Morris' water maze learning abilities were assessed throughout a 35-day survival period. Subsequently, acetylcholinesterase (AChE) histochemistry was used to visualize alterations of parietal cortical cholinergic innervation. In response to the neurotoxic action of beta-amyloid(Phe(SO3H)24)25-35, a progressive hyperactivity developed in the rats in their home cages which were maintained throughout the 5-week post-injection period. This was accompanied by a significant hypoactivity in the novel environment of a locomotor arena. Beta-amyloid(Phe(SO3H)24)25-35-treated animals showed greatly impaired cortical memory functions in the step-through passive shock-avoidance paradigm, while spatial learning processes remained unaffected. Moreover, beta-amyloid(Phe(SO3H)24)25-35 injections in the nucleus basalis suppressed explorative behavior in rats and inhibited conditioned stress responses 28 days after surgery. Reductions of cortical cholinergic (AChE-positive) projections provided anatomical substrate for the behavioral changes. This indicated extensive, long-lasting neurodegenerative processes as a result of beta-amyloid(Phe(SO3H)24)25-35 infusion.
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PMID:Beta-amyloid(Phe(SO3H)24)25-35 in rat nucleus basalis induces behavioral dysfunctions, impairs learning and memory and disrupts cortical cholinergic innervation. 958 Feb 73

Acetylcholinesterase (AChE), the enzyme involved in the hydrolysis of the neurotransmitter acetylcholine, has been implicated in non-cholinergic actions which may play a role in neurodegenerative diseases such as Alzheimer's disease. To study the potential cytotoxicity of brain AChE, the effects of affinity purified AChE were analyzed on neuronal (Neuro 2a) and glial-like (B12) cells. LDH release and MTT reduction assays showed that AChE was toxic; the toxicity was dependent on the enzyme concentration, time of incubation and cellular density. The toxic effect of AChE was not related to its catalytic activity, since the anti-cholinesterase drug BW284C51 and heat inactivation were unable to block the effects of the enzyme. When cells were incubated at 4 degrees C, toxicity was completely blocked, in contrast to cells incubated at 37 degrees C. The presence of serum in the culture medium inhibited the toxic effects of AChE. Cytoplasmic shrinkage, condensation and fragmentation of nucleus as well as DNA strand breaks detected with the TUNEL technique indicated that apoptotic cell death is involved in the effect of AChE. Considering that we have previously shown that AChE promotes the assembly of beta-amyloid peptide into neurotoxic amyloid fibrils, it is conceivable that the neurotoxicity of AChE shown here may play a role in the neuronal degeneration observed in Alzheimer's disease.
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PMID:Toxic effects of acetylcholinesterase on neuronal and glial-like cells in vitro. 967


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