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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer's disease (AD) resulted in three drugs being registered for the first time in the US and Europe. All three compounds are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a stable level during a 6-month to 1-year period of treatment, as compared to placebo. Additional drug effects are to slow down cognitive deterioration and improve behavioral and daily living activity. Recent studies show that in many patients the cognitive stabilization effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic, and directly cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and amyloid precursor protein (APP) metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and cholinergic synaptic function; the effect of such lesions can be reversed by ChEI treatment. A reduction in cholinergic neurotransmission, experimental or pathological, leads to amyloidogenic metabolism and contributes to the development of neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, for which evidence is available on an experimental as well as clinical level, a mechanism based on beta-amyloid metabolism is postulated. The question whether cholinergic stabilization implies simply slowing down progression of disability or also involves delay of disease progression is discussed.
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PMID:Is anti-cholinesterase therapy of Alzheimer's disease delaying progression? 1144 6

Amyloid beta peptide implicated in Alzheimers disease is cleaved by insulin degrading enzyme (IDE). Abnormal cholinesterases similar to butyrylcholinesterase (BChE) are found in Alzheimer brain. The similarities between IDE and BChE (which is known to have an arylacylamidase and a metallocarboxypeptidase-like activity) such as their zinc metalloenzyme nature, their localization in glia and their ability to bind amyloid peptide in Alzheimers disease raise interesting questions.
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PMID:Amyloid beta peptide processing, insulin degrading enzyme, and butyrylcholinesterase. 1149 57

1. Acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BuChE, EC 3.1.1.8) are enzymes that catalyze the hydrolysis of esters of choline. 2. Both AChE and BuChE have been shown to copurify with peptidases. 3. BuChE has also been shown to copurify with other proteins such as transferrin, with which it forms a stable complex. In addition, BuChE is found in association with beta-amyloid protein in Alzheimer brain tissues. 4. Since BuChE copurifies with peptidases, we hypothesized that BuChE interacts with these enzymes and that this association had an influence on their catalytic activities. One of the peptidases that copurifies with cholinesterases has specificity similar to trypsin, hence, this enzyme was used as a model to test this hypothesis. 5. Purified BuChE causes a concentration-dependent enhancement of the catalytic activity of trypsin while trypsin does not influence the catalytic activity of BuChE. 6. We suggest that, in addition to its esterase activity, BuChE may assume a regulatory role by interacting with other proteins.
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PMID:Butyrylcholinesterase-Mediated enhancement of the enzymatic activity of trypsin. 1156 38

Alzheimer disease (AD) is characterized pathologically by cholinergic deficits, amyloid plaques, neurofibrillary tangles, gliosis, and neuronal and synaptic loss. The primary therapeutic approach that has arisen from the pathological analysis of AD brain has been cholinergic augmentation by cholinesterase inhibitors, which modestly improve cognitive function. Research on the underlying pathophysiological dysfunction have focussed on AD-specific processes such as amyloid precursor protein, tau, and cerebral apolipoprotein E metabolism, and more general neurodegenerative processes such as inflammation, oxidation, excitotoxicity, and apoptosis. Rational neuroprotective approaches have led to recent trials of estrogen, antioxidant and anti-inflammatory medications in AD, and to the development of anti-amyloid strategies for delaying progression or preventing development of AD.
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PMID:Alzheimer disease therapeutics. 1158 22

The introduction of cholinesterase inhibitors to improve the cognitive function and activities of daily living in patients with Alzheimer disease, raises the question whether these drugs also have the potential to improve the quality of life of these patients. In this article a model is presented to measure quality of life in patients with dementia, in which psychological well-being is chosen as the central measure. The presented model might be the starting point to develop instruments to measure quality of life in dementia. After a short introduction concerning the developments in quality of life research, the two most important characteristics of the concept--multidimensionality and subjectivity--are discussed against the background of the relevant literature on dementia. The dementia-specific dimensions--individual characteristics, psychological, social and physical dimension, and environment--and domains are presented, and put in a hierarchical model.
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PMID:[Quality of life and dementia. I. Model of assessment of wellbeing in dementia patients]. 1178 14

Recent studies in cell cultures have shown that modulating the cholinergic activity can influence the processing and metabolism of amyloid precursor protein (APP). To investigate whether acetylcholinesterase inhibitors (ChEIs) could decrease production of amyloid beta-peptide (A(beta)) and slow down the accumulation of A(beta) also in vivo, we chronically administered metrifonate (100 mg/kg, po), a second-generation ChEI, to 7-month-old doubly transgenic APP+PS1 mice and their nontransgenic littermate controls for 7 months. Behavioral studies, including open field test, T maze, and water maze, were conducted after 6 months treatment with metrifonate, and the mice were sacrificed at the age of 14 months for biochemical and histological analyses. The long-term treatment with metrifonate failed to inhibit the marked overproduction and deposition of A(beta) in the APP+PS1 mice; in contrast, it increased both A(beta)40 and A(beta)42 levels in the hippocampus. However, the A(beta)42 to 40 ratio was significantly reduced by the treatment. In addition, the number of amyloid plaques in the hippocampus did not differ between the treatment and the control groups. Tolerance to cholinesterase inhibition might be induced in the mouse brain because the inhibition rate of AChE was attenuated from about 80 to 50% during the experiment in both APP+PS1 and nontransgenic mice. The metrifonate treatment did not affect cognitive testing parameters but reduced swimming speed and locomotor activity in both genotypes. Our results do not support the idea that ChEIs would slow down the progression of amyloid pathology in Alzheimer's disease.
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PMID:The effects of long-term treatment with metrifonate, a cholinesterase inhibitor, on cholinergic activity, amyloid pathology, and cognitive function in APP and PS1 doubly transgenic mice. 1182 83

The incidence, distribution and chemical composition of amyloid-beta (A beta) peptide-positive deposits were investigated in the lower primate species common marmoset (Callithrix jacchus). No A beta deposits were observed in the brains of 7 marmosets below 7 years of age. In 15 marmosets above 7 years, 60% displayed cortical A beta-immunoreactive plaques, 80% had A beta deposited in intracortical vessels and 87% displayed A beta deposits in meningeal vessels. The cerebral cortex of the oldest animal (15 years) contained a substantial density of deposits. A beta-immunoreactive plaques were found predominantly in association cortical zones followed by a lower density in paralimbic cortical areas. Deposits within vessels were most frequent in occipital cortex. A beta40 was found primarily in vascular deposits, while A beta42 was present in plaques. Approximately 20% of plaques and most vascular deposits displayed thioflavin S staining, indicative of the presence of fibrillar A beta. Varying proportions of A beta deposits contained acetylcholinesterase or butyrylcholinesterase activities and apolipoprotein E and alpha1-antichymotrypsin immunoreactivity. A few plaques contained immunoreactivity for amyloid precursor protein in swollen neurites. However, no abnormally phosphorylated tau immunoreactivity was present in these neurites. Survival analysis in a colony of marmosets indicated that only 6% of animals can be expected to survive beyond 7 years of age. These results indicate that the aged marmoset brain displays A beta deposits with a distribution and chemical composition similar to those found in the human. These similarities suggest that the aged marmoset may be a useful lower primate model for the study of the pathological effects of A beta. However, the relatively small number of animals which can be expected to reach old age severely limits the utility of this species as a model of A beta deposition.
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PMID:Amyloid-beta deposits in the cerebral cortex of the aged common marmoset (Callithrix jacchus): incidence and chemical composition. 1183 47

In the past 2 years, substantive advances in therapy for Alzheimer's disease (AD) have occurred. The nature of the effects of cholinesterase inhibitors has been refined with the publication of several studies that have examined different aspects of the symptomatology of AD. Breakthroughs in the basic science of Alzheimer's disease have led to new insights into potential therapeutic strategies targeted at the secretases involved in the metabolism of the Alzheimer precursor protein. An immunization approach, in which the beta-amyloid protein itself was used as the immunizing agent, has also been presented and independently validated. Other areas of investigation with disappointing results, such as estrogen replacement therapy, anti-inflammatory approaches, and several other therapeutic agents, are also reviewed.
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PMID:Pharmacotheraphy for Alzheimer's disease. 1189 53

Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and anti-apoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [(N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S-enantiomer TV3279 [(N-Propargyl-(3S)Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The anti-apoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glyceraldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PKI 1195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by rasagiline and TV3326 is closely linked to the anti-apoptotic action of these drugs and their ability to process APP by activation of alpha-secretase.
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PMID:Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. 1204 33

In the nonamyloidogenic processing pathway the Alzheimer s amyloid precursor protein (APP) is proteolytically cleaved by alpha-secretase. As this cleavage occurs at the Lys16-Leu17 bond within the amyloid beta domain, it prevents deposition of intact amyloidogenic peptide. In addition, the large ectodomain (sAPP(alpha)) released by the action of alpha-secretase has several neuroprotective properties. Studies with a range of hydroxamic acid-based compounds, such as batimastat, indicate that alpha-secretase is a zinc metalloproteinase, and members of the adamalysin family of proteins, TACE, ADAM10 and ADAM9, all fulfil some of the criteria required of alpha-secretase. APP is constitutively cleaved by alpha-secretase in most cell lines. However, on stimulation with muscarinic agonists or activators of protein kinase C, such as phorbol esters, the alpha-secretase cleavage of APP is up-regulated. The constitutive alpha-secretase activity is primarily at the cell surface, while the regulated activity is predominantly located within the Golgi. The beneficial action of cholinesterase inhibitors may in part be due to activation of muscarinic receptors, resulting in an up-regulation of alpha-secretase. Other agents can also increase the nonamyloidogenic cleavage of APP including estrogen, testosterone, various neurotransmitters and growth factors. As the alpha-secretase cleavage of APP both precludes the deposition of the amyloid beta peptide and releases the neuroprotective sAPP(alpha), pharmacological up-regulation of alpha-secretase may provide alternative therapeutic approaches for Alzheimer s disease.
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PMID:The search for alpha-secretase and its potential as a therapeutic approach to Alzheimer s disease. 1205 75


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