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)

We used the ELISA to measure the concentration of amyloid protein precursor with Kunitz type trypsin inhibitor domains (APPI) in CSF of dementia of the Alzheimer type (DAT) and examined the correlation of APPI with acetylcholinesterase (AChE) and somatostatin (SRIF). We found the APPI concentration in CSF of DAT to be significantly elevated compared with that of multi-infarct dementia and controls. We could significantly correlate APPI with AChE, but not correlate APPI with SRIF. The present results suggest that measurement of CSF APPI levels may be useful for diagnosis of DAT and the change of APPI may closely be associated with abnormality of acetylcholine system in DAT that has been reported.
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PMID:Amyloid beta protein precursors with kunitz-type inhibitor domains and acetylcholinesterase in cerebrospinal fluid from patients with dementia of the Alzheimer type. 137 55

The colocalization of beta amyloid protein with the enzymes acetyl- and butyrylcholinesterase was assessed using immunocytochemistry for beta amyloid protein and a sensitive histochemical technique for cholinesterases. In non-demented aged and Alzheimer's disease brains, double-stained sections for cholinesterases and thioflavin-S showed that all thioflavin-S-positive plaques were also positive for cholinesterases, indicating the presence of these enzymes in all plaques with beta-pleated amyloid protein. When amyloid angiopathy was present, cholinesterases were also observed in amyloid-laden vessels walls. Comparison of series of adjacent sections alternatively stained for acetylcholinesterase, beta amyloid protein and butyrylcholinesterase, as well as by double histo-immunocytochemical staining, showed either cholinesterase in a proportion of the preamyloid diffuse plaques. These data indicate that cholinesterases are associated with the amyloid protein from very early stages, when the beta-pleated structure is being formed. Novel functions attributed to acetyl- and butyrylcholinesterase, such us their proteolytic activity either by themselves or in association with heparan sulfate proteoglycans, may play a role in the aggregation or the consolidation processes taking place at the early stages of diffuse plaque formation.
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PMID:Colocalization of cholinesterases with beta amyloid protein in aged and Alzheimer's brains. 848 May 10

A protease activity which co-purified with affinity-purified fetal bovine serum acetylcholinesterase (AChE) has been shown to release the amyloid protein precursor (APP) of Alzheimer's disease from cell membranes. The nature of this protease and its relationship to AChE have not been established. In this study, the protease activity was found to be recovered with a minor dimeric form of AChE. This minor form (AChEII) was distinguished from the more abundant tetrameric form (AChEI) by a higher catalytic subunit relative molecular mass (M(r)) of 80,000 (80K), and by a lower affinity for edrophonium-Sepharose. The difference in subunit M(r) was due to differing degrees of glycosylation, as deglycosylation of both AChEI and AChEII gave rise to a similar subunit M(r) of 62K. The protease activity recovered with AChEII was not an intrinsic property of the esterase, as it was separated from the esterase by anion-exchange chromatography, and by immunoprecipitation with anti-AChE antibodies. AChEI possessed a similar subunit M(r) to the tetrameric form of AChE secreted from the bovine adrenal gland, while AChEII possessed a similar subunit molecular weight to the dimeric membrane-bound form of bovine erythrocyte AChE. Thus, it is possible that AChEII may be a solubilised form of a dimeric glycosylphosphatidyl inositol-linked AChE.
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PMID:A protease is recovered with a dimeric form of acetylcholinesterase in fetal bovine serum. 851 52

Alzheimer's disease (AD) is characterized in the brain by the deposition of amyloid protein outside the neuron, resulting in the formation of plaques, and inside the neuron with neurofibrillary tangles. It is not yet known what causes these pathologic changes, although age and genetics are major risk factors. The cholinesterase inhibitors tacrine and donepezil block acetylcholinesterase and therefore preserve the neurotransmitter acetylcholine. Three other investigational cholinesterase inhibitors are rivastigmine, metrifonate, and galanthamine. Existing therapies being studied for use in AD include vitamin E, estrogen preparations, and anti-inflammatory agents. The physician's role is to care for both the AD patient and the family, which are profoundly affected by this disease.
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PMID:Alzheimer's disease: seeking new ways to preserve brain function. Interview by Alice V. Luddington. 1002 72

An animal model of non-hereditary AD was built by lesioning nucleus basalis of Meynert (nbM) and to investigate the behavioral alteration by Morris water maze, the pathological changes by special staining for senile plaques(SPs), enzymatic cytochemical staining for AChE, and immunocytochemical staining for beta amyloid protein (beta AP) and tau protein. Transmission electron microscopic observation has also been made. Results showed: (1) loss of learning and memory ability; (2) occurrence of necrotic granules in cytoplasm and inclusion in axon hillock; accumulation of necrotic cell, and formation of SPs under light microscope; (3) accumulation of microtubules and formation of inclusion, increase of lysosome and edema and vacuolation of neurons and neuroterminals under electron microscopy; (4) decrease of synaptic density; (5) sharp decrease of AChE (acetylcholinesterase) positive fibers and neurons shown by immunocytochemical staining; (6) overexpression of beta AP and tau protein.
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PMID:[An animal model of non-hereditary Alzheimer's disease and its behavioral and pathologic changes]. 1103 83

Alzheimer's disease is the most frequent form of dementia and it is estimated that its prevalence will quadruple by the year 2050. In the past decade, a number of important new developments have provided insight in the pathogenesis, improved diagnosis and allowed therapy of dementia. Several new mutations in the amyloid protein precursor gene, presenilin-1 and -2 genes and the influence of the apolipoprotein E gene isotypes on the disease phenotype have been described. The role of secretases in the generation of amyloid in senile plaques has been determined and this may provide important new therapeutic approaches in the future. The role of vascular lesions in the development of dementia and relationship with the Lewy body variant of Alzheimer's disease have been refined. Acetylcholine is deficient in Alzheimer's disease and can be supplemented in part by treatment with acetylcholinesterase inhibitors. Recently, surprising results of vaccination with amyloid in a transgenic mouse model have opened a completely new perspective in the prevention and treatment of Alzheimer's disease.
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PMID:Recent developments in Alzheimer's disease. 1177 Feb 21

Alzheimer's disease (AD) is a neurodegenerative disorder with progressive dementia accompanied by two main structural changes in the brain: intracellular protein deposits termed neurofibrillary tangles (NFT) and extracellular amyloid protein deposits surrounded by dystrophic neurites that constitutes the senile plaques. Currently, it is widely accepted that amyloid beta-peptide (A beta) metabolism disbalance is crucial for AD progression. A beta deposition may be enhanced by molecular chaperones, including metals like copper and proteins like acetylcholinesterase (AChE). At the neuronal level, several AD-related proteins interact with transducers of the Wnt/beta-catenin signaling pathway, including beta-catenin and glycogen synthase kinase 3 beta (GSK-3 beta) and both in vitro and in vivo studies suggest that Wnt/beta-catenin signaling is a target for A beta toxicity. Accordingly, activation of this signaling by lithium or Wnt ligands in AD-experimental animal models or in primary hippocampal neurons attenuate A beta neurotoxicity by recovering beta-catenin levels and Wnt-target gene expression of survival genes such as bcl-2. On the other hand, peroxisomal proliferator-activated receptor gamma (PPAR gamma) and muscarinic acetylcholine receptor (mAChR) agonists also activate Wnt/beta-catenin signaling and they have neuroprotective effects on hippocampal neurons. Our studies are consistent with the idea that a sustained loss of function of Wnt signaling components would trigger a series of events, determining the onset and development of AD and that modulation of this pathway through the activation of cross-talking signaling cascades should be considered as a possible therapeutic strategy for AD treatment.
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PMID:Signal transduction during amyloid-beta-peptide neurotoxicity: role in Alzheimer disease. 1557 77

Current mouse models of Alzheimer's disease show brain pathology that correlates to a degree with memory impairment, but underlying molecular mechanisms remained unknown. Here we report studies with three lines of transgenic mice: animals that doubly express mutated human amyloid precursor protein (APPswe) and human acetylcholinesterase (hAChE); and animals transgenic for only the APPswe or the hAChE. Among these genotypes, variations were observed in expression of mRNA for presenilin-1, which was highest in singly transgenic hAChE mice, and the stress-inducible form of AChE, which was elevated when both transgenes were present. At the age of nine months, both double and single transgenic mice displayed working memory impairment in a radial arm water maze. However, as compared with mice expressing amyloid alone, the double transgenic animals exhibited more numerous plaques and greater amyloid burden in brain (both by histochemistry and by ELISA of amyloid protein). Moreover, the amyloid burden in double transgenics was tightly correlated with memory impairment as measured by total maze errors (r2= 0.78, p = .002). This correlation was markedly stronger than observed in mice with amyloid alone. These new findings support the notion of cholinergic-amyloid interrelationships and highlight the double transgenic mice as a promising alternative for testing Alzheimer's therapies.
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PMID:Memory deficits correlating with acetylcholinesterase splice shift and amyloid burden in doubly transgenic mice. 1597 94

Beta amyloid protein (Abeta) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)-tacrine, a novel dimeric AChE inhibitor, on Abeta-induced neurotoxicity in primary cortical neurons. Bis(7)-tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation. Both nicotinic and muscarinic receptor antagonists failed to block the effects of bis(7)-tacrine. Instead, nimodipine, a blocker of L-type voltage-dependent Ca2+ channels (VDCCs), attenuated Abeta neurotoxicity, whereas N-, P/Q- or R-type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca2+ imaging assay revealed that, similar to nimodipine, bis(7)-tacrine reversed Abeta-triggered intracellular Ca2+ increase, which was mainly contributed by the extracellular Ca2+ instead of endoplasmic reticulum and mitochondria Ca2+. Concurrently, using whole cell patch-clamping technique, it was found that bis(7)-tacrine significantly reduced the augmentation of high voltage-activated inward calcium currents induced by Abeta. These results suggest that bis(7)-tacrine attenuates Abeta-induced neuronal apoptosis by regulating L-type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.
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PMID:Bis(7)-tacrine attenuates beta amyloid-induced neuronal apoptosis by regulating L-type calcium channels. 1677 27

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a low amount of acetylcholine (ACh) in hippocampus and cortex. Acetylcholinesterase (AChE) is one of the most important enzymes in many living organisms including human being and other vertebrates, insects like mosquitoes, among others. Several reports have been published where it has been clearly shown that the genesis of amyloid protein plaques associated with AD is connected to modifications of both AChE and butyrylcholinesterase (BChE), since the plaque is significantly decreased in AD patients using cholinesterase inhibitors (ChEIs). This review gives some examples of these inhibitors discovered during past couple of years that have shown very prominent interactions at the active site triad of the proteins as well as different other parts of the active site like, peripheral anionic site (PAS), oxyanionic hole, anionic subsite or acyl binding pocket (ABP). Most of the inhibition and their interactions have been visualized by X-ray crystallography, but some of the other inhibitors have been studied either by molecular docking or molecular dynamic (MD) simulations or by both the in silico methods. Some of these prominent studies have been crucially observed and reported here.
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PMID:Molecular interactions of cholinesterases inhibitors using in silico methods: current status and future prospects. 1949 Oct 49


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