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

---

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

Alteration in the processing of the amyloid precursor protein (APP) is a central event in the formation of amyloid deposits in the brains of individuals with Alzheimer's disease (AD). It has been suggested that acetylcholinesterase (AChE) inhibitors, which promote the cholinergic function and consequently improve the cognitive deficits, may also exert a neuroprotective effect by activating normal APP processing. We now report that an irreversible AChE inhibitor (metrifonate) increase the cell-associated APP level in a basal forebrain neuronal culture and also elevate the amount of APP secreted into the medium. The alterations in APP processing were accompanied by increased protein kinase C (PKC) levels. The results suggest that AChE inhibitors modulate the metabolism of APP, possibly via their stimulatory effects on PKC. Since changes in the activity and level of PKC may be involved in the pathogenesis of AD, it is concluded that the beneficial effect of metrifonate in AD therapy may be due not only to the stimulatory cholinergic function, but also to its activating effect on PKC.
...
PMID:In vitro effects of metrifonate on neuronal amyloid precursor protein processing and protein kinase C level. 1077 17

Cholinesterase inhibitors tested in clinical trials in Europe, the United States, and Japan include fewer than 10 drugs; however, most of these compounds have advanced to clinical phase III trials. Based on results related to a population of more than 8,000 patients, we conclude that several of these compounds have shown significant clinical efficacy and safety in the treatment of Alzheimer disease. There are, however, differences with regard to side effects. The major clinical effect is stabilization of cognitive function during a 6- to 12-month period with an improvement of behavioral symptoms. The long-term effect of cholinesterase inhibitors extending to a 2-year period was reported. Future applications of these drugs include treatment of other types of dementias such as Lewy bodies dementia, vascular dementia, and Down syndrome dementia. The combination of cholinesterase inhibitors with estrogens, antioxidants, and anti-inflammatories may represent a further improvement of the therapy. From an economical point of view, treatment with cholinesterase inhibitors is not cost neutral.
...
PMID:Cholinesterase inhibitor therapy stabilizes symptoms of Alzheimer disease. 1085 Jul 24

Dementia resulting from Alzheimer disease is one of the most prevalent medical problems. Elaborate expert guidelines for the diagnosis and treatment of Alzheimer disease do not always take sufficient account of the resources available in general practice. The focus on pure Alzheimer disease can be inappropriate for the large proportion of mixed dementia cases in old age. Because of such guidelines, treatment with modern and effective drugs is often delayed until conservative dementia criteria are satisfied. Criteria for the discontinuation of antidementia drugs are highly questionable. Antidementia drug sales in Germany demonstrate that the majority of prescribers hold on to conservative attitudes and prefer Ginkgo biloba and memantine to acetylcholinesterase inhibitors. Disappointment after exaggerated expectations and financial restrictions in the health care sector may aggravate current underprescribing of antidementia drugs. Even though contemporary symptomatic treatments for Alzheimer disease are unsatisfactory, modern medicine has been very successful in the early diagnosis and treatment of other potential causes of dementia. Future strategies will include models for the early identification of individuals carrying a high risk of developing cognitive impairment during their lifetime.
...
PMID:Clinical issues in current drug therapy for dementia. 1085 Jul 37

Brain acetylcholinesterase activity was measured in 14 patients with Alzheimer disease and 14 age-matched control subjects by positron emission tomography with a radioactive acetylcholine analogue. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala of all patients with Alzheimer disease, suggesting a loss of cholinergic innervation from the basal forebrain. Most profound reductions of k3 values were observed in the temporal (-30%) and parietal cortices (-31%), although reductions of k3 values were relatively uniform in the cerebral neocortex. This technique may be a powerful tool for early diagnosis of Alzheimer disease and also for therapeutic monitoring of acetylcholinesterase inhibitors in Alzheimer disease.
...
PMID:Brain acetylcholinesterase activity in Alzheimer disease measured by positron emission tomography. 1085 Jul 39

In Alzheimer disease, therapies to improve the core symptoms and perhaps even slow disease progression include cholinesterase inhibitors, receptor agonists, antiinflammatory drugs, and antioxidants. Neuroleptics, antiepileptics, and nondrug approaches are used to control and relieve complications such as delusions, hallucinations, paranoia, and agitated behavior. We outline a practical approach to the use of these therapies.
...
PMID:Effective treatment of Alzheimer disease and its complications. 1086 Feb 27

Several lines of evidence implicate a cholinergic deficit in Alzheimer's disease (AD). Transgenic mice that overexpress clinical mutants of the human amyloid precursor protein (APP) have been generated that recapitulate many aspects of AD. We now analyzed the cholinergic system in aged APP/London transgenic mice. The major finding was the reorganization of acetylcholinesterase-positive fibers within the hippocampus and the reduced size of cholinergic cells in the medial septum. The reduction of acetylcholinesterase-positive fibers in the subiculum together with increased fiber density in the CA1 and in the dentate gyrus suggests a synaptic sprouting compensatory mechanism within the hippocampus. In the cortex, amyloid plaques were associated with intense acetylcholinesterase activity and surrounded by dystrophic acetylcholinesterase-positive fibers. Nevertheless, the overall pattern of cholinergic innervation was unchanged. These results demonstrate that overexpression of APP/London caused, besides amyloid plaques in aged mouse brain, also cholinergic deafferentation and cholinergic cell shrinkage.
...
PMID:Acetylcholinesterase-positive fiber deafferentation and cell shrinkage in the septohippocampal pathway of aged amyloid precursor protein london mutant transgenic mice. 1086 Jul 82

Alzheimer's disease (AD) pathology is characterized by A beta peptide-containing plaques, neurofibrillary tangles consisting of hyperphosphorylated tau, extensive neuritic degeneration, and distinct neuron loss. We generated several transgenic mouse lines expressing the human amyloid precursor protein (APP751) containing the AD-linked KM670/671NL double mutation (Swedish mutation) under the control of a neuron-specific Thy-1 promoter fragment. In the best APP-expressing line (APP23), compact A beta deposits can be detected at 6 months of age. These plaques dramatically increase with age, are mostly Congo Red positive, and accumulate typical plaque-associated proteins such as heparansulfate proteoglycan and apolipoprotein E. Activated astrocytes and microglia indicative of inflammatory processes reminiscent of AD accumulate around the deposits. Furthermore, plaques are surrounded by enlarged dystrophic neurites as visualized by neurofilament or Holmes-Luxol staining. Strong staining for acetylcholinesterase activity is found throughout the plaques and is accompanied by local distortion of the cholinergic fiber network. All congophilic plaques contain hyperphosphorylated tau reminiscent of early tau pathology. Modern stereologic methods demonstrate a significant loss of neurons in the hippocampal CA1 region, correlating with an increasing A beta plaque load. Interestingly, APP23 mice develop cerebral amyloid angiopathy in addition to amyloid plaques even though the APP transgene is only expressed in neurons. Crossbreeding of APP23 mice with transgenic mice carrying AD-linked presenilin mutations but not wild-type presenilin resulted in enhanced formation of pathology. In conclusion, our APP transgenic mice present many pathologic features, similar to those observed in AD and therefore offer excellent tools for studying the contribution of A beta to AD pathogenesis.
...
PMID:Transgenic mouse models of Alzheimer's disease. 1091 65

Three major lines of drugs have been developed or are under development for the treatment of Alzheimer Disease (AD): cholinergic drugs (mainly cholinesterase inhibitors), anti-beta-amyloid drugs, estrogens and anti-inflammatories. Cholinesterase inhibitors are the only drugs presently approved in USA and Europe for the indication of AD. Cholinesterase inhibitors tested in clinical trials in Europe, USA and Japan include less than ten drugs, however most of these compounds have advanced to clinical trials III. Based on results related to a population of over 8,000 patients we conclude that several of these compounds have shown significant clinical efficacy and safety in the treatment of Alzheimer disease. There are, however, differences with regard to side effects. The major clinical effect is stabilization of cognitive function during a six- to 12-months period with a parallel improvement of behavioral symptoms. Long-term effect of cholinesterase inhibitors extending to a two year-period has been reported. Future applications of these drugs are treatment of other types dementias such as Lewy body dementia, vascular dementia and Down Syndrome dementia. Combination of cholinesterase inhibitors with estrogens, anti-oxidants and anti-inflammatories may represent a further improvement of the therapy. From the economical point of view, treatment with cholinesterase inhibitors is not cost neutral.
...
PMID:Present and future of Alzheimer therapy. 1096 34

Immunohistochemistry was used to analyse 18- and 26-month-old transgenic mice overexpressing the human beta-amyloid precursor protein under the platelet-derived growth factor-beta promoter with regard to presence and distribution of neuropeptides. In addition, antisera/antibodies to tyrosine hydroxylase, acetylcholinesterase, amyloid peptide, glial fibrillary acidic protein and microglial marker OX42 were used. These mice have been reported to exhibit extensive amyloid plaques in the hippocampus and cortex [Masliah et al. (1996) J. Neurosci. 16, 5795-5811]. The most pronounced changes were related to neuropeptides, whereas differences between wild-type and transgenic mice were less prominent with regard to tyrosine hydroxylase and acetylcholinesterase. The main findings were of two types; (i) involvement of peptide-containing neurites in amyloid beta-peptide positive plaques, and (ii) more generalized changes in peptide levels in specific layers, neuron populations and/or subregions in the hippocampal formation and ventral cortices. In contrast, the parietal and auditory cortices were comparatively less affected. The peptide immunoreactivities most strongly involved, both in plaques and in the generalized changes, were galanin, neuropeptide Y, cholecystokinin and enkephalin. This study shows that there is considerable variation both with regard to plaque load and peptide expression even among homozygotes of the same age. The most pronounced changes, predominantly increased peptide levels, were observed in two 26-month-old homozygous mice, for example, galanin-, enkephalin- and cholecystokinin-like immunoreactivities in stratum lacunosum moleculare, and galanin, neuropeptide Y, enkephalin and dynorphin in mossy fibers. Many peptides also showed elevated levels in the ventral cortices. However, decreases were also observed. Thus, galanin-like immunoreactivity could not any longer be detected in the diffusely distributed (presumably noradrenergic) fiber network in all hippocampal and cortical layers, and dynorphin-like immunoreactivity was decreased in stratum moleculare, cholecystokinin-like immunoreactivity in mossy fibers and substance P-like immunoreactivity in fibers around granule cells. The significance of generalized peptide changes is at present unclear. For example, the increase in the mainly inhibitory peptides galanin, neuropeptide Y, enkephalin and dynorphin and the decrease in the mainly excitatory peptide cholecystokinin in mossy fibers (and of substance P fibers around granule cells) indicate a shift in balance towards inhibition of the input to the CA3 pyramidal cell layer. Moreover, it may be speculated that the increase in levels of some of the peptides represents a reaction to nerve injury with the aim to counteract, in different ways, the consequences of injury, for example by exerting trophic actions. Further studies will be needed to establish to what extent these changes are typical for Alzheimer mouse models in general or are associated with the V717F mutation and/or the platelet-derived growth factor-beta promoter.
...
PMID:Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein--initial observations. 1100 66

Alzheimer's disease is the most common cause of memory disruption in elderly people. The main pathogenic factor of the disease is beta-amyloid protein, which may cause toxic damage of neurones. Other suggested pathogenic factors include an inflammatory process around the senile plaques, apoptosis and necrotic death of neurones, and, in consequence, changes in functioning of neurotransmitter systems. In this article the authors present the main directions in pharmacotherapy of Alzheimer's disease: causal therapy, which prevents the neurodegenerative changes and slows down the pathogenetic process, and symptomatic therapy. The aim of symptomatic therapy is to reduce memory disruption and psychiatric symptoms associated with the disease. Positive influence on cognitive processes is exerted by cholinergic drugs, e.g. the actually used inhibitors of acetylcholinesterase (rivastigmine, donepezil), the nootropic agents (piracetam, nefiracetam) and extracts of Gingko biloba. For treatment of the disease accompanying psychiatric symptoms (anxiety, depression, hallucinations, sleepness) the drugs with minimal influence on cognitive processes are recommended. Attempts at causal therapy are focussed on searching for the substances that can prevent the formation and toxicity of beta-amyloid (droloksifen, estrogens, agonists of muscarinic receptors M1), the cytotoxic influence of excitatory aminoacids (memantine, lamotrigine), calcium (nimodipine) and free radicals (selegiline, alpha-tocoferol), and the development of inflammatory process (non-steroidal antiinflammatory drugs). The new target of research is correction of deficits of nerve growth factor and neurotransmitters by intracerebral implantation of modified fibroblasts. Another way is prevention of the formation of amyloid plaques using appropriate antisense oligonucleotides.
...
PMID:[Perspectives of therapy of Alzheimer's disease]. 1105 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---