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 measured CSF acetylcholinesterase (AChE) activity in 57 Alzheimer's disease (AD) patients with different apolipoprotein E (apoE) genotypes at the early stage of the disease, and in 11 non-demented controls. The AChE activities of the whole AD group did not differ from those of controls. However, analysis of variance over the AD subgroups with two, one or no epsilon4 alleles and controls showed significant differences (p < 0.0001); the AD patients with two epsilon4 alleles had higher AChE activities than controls and AD patients with one or no epsilon4 and also the AD patients carrying one epsilon4 allele had higher AChE activities than the AD patients without the epsilon4 allele. The study suggests that cholinergic metabolism is altered in proportion to the number of apoE epsilon4 alleles. The different degree of AChE activity in relation to the number of epsilon4 alleles might have an impact on AD patients' responses to cholinesterase inhibitors.
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PMID:Increased acetylcholinesterase activity in the CSF of Alzheimer patients carrying apolipoprotein epsilon4 allele. 874 53

Recent studies suggest that apolipoprotein E (apoE) plays a specific role in brain cholinergic function and that the E4 allele of apoE (apoE4), a major risk factor for Alzheimer's disease (AD), may predict the extent of cholinergic dysfunction and the efficacy of cholinergic therapy in this disease. Animal model studies relevant to this hypothesis revealed that apoE-deficient (knockout) mice have working memory impairments that are associated with distinct dysfunction of basal forebrain cholinergic neurons. Cholinergic replacement therapy utilizing M1-selective muscarinic agonists has been proposed as effective treatment for AD patients. In the present study, we examined whether the memory deficits and brain cholinergic deficiency of apoE-deficient mice can be ameliorated by the M1-selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline), [AF150(S)]. Treatment of apoE-deficient mice with AF150(S) for 3 weeks completely abolished their working memory impairments. Furthermore, this reversal of cognitive deficit was associated with a parallel increase of histochemically determined brain choline acetyltransferase and acetylcholinesterase levels and with the recovery of these cholinergic markers back to control levels. These findings show that apoE deficiency-related cognitive and cholinergic deficits can be ameliorated by M1-selective muscarinic treatment. They also provide a novel model system for development and evaluation of therapeutic strategies directed specifically at the AD patients whose condition is attributed to the apoE genotype.
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PMID:M1 muscarinic agonist treatment reverses cognitive and cholinergic impairments of apolipoprotein E-deficient mice. 957 84

The effect of long-term treatment with tacrine (tetrahydroaminoacridine) was studied in three Alzheimer patients (aged 57, 64, and 68 years) with mild dementia. All three patients had a Mini-Mental State Examination score of 24/30 and carried at least one apolipoprotein E (ApoE) epsilon4 allele. Tacrine was given in doses between 80 and to 160 mg daily for 13-31 months. A lower tacrine concentration was observed generally in cerebrospinal fluid (CSF) compared with plasma. The acetylcholinesterase activity in CSF tended to be increased following longer periods of tacrine treatment, whereas the butyrylcholinesterase activity was decreased. The three patients repeatedly underwent positron emission tomography investigation of cerebral blood flow, nicotinic receptors, cerebral glucose metabolism, and electroencephalogram (EEG) and cognitive tests. Positive influences on these parameters were observed following both short-term and long-term treatment with tacrine. Improvement of nicotinic receptors (measured as 11C-nicotine binding), cerebral blood flow, EEG, and some cognitive tests (trail making test, block design test) occurred earlier after initiation of tacrine treatment compared with the glucose metabolism, which was increased after several months of tacrine treatment. An improvement in attention (trail making test) was observed following tacrine as sign for frontal lobe activation (EEG). The functional effects of tacrine in Alzheimer patients appeared to be related to both dose and length of cholinesterase inhibitor treatment.
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PMID:Long-term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities. 977 28

Butyrylcholinesterase (BChE) as well as acetylcholinesterase has been suggested to be associated with Alzheimer's disease (AD). Lehmann et al. [1997: Hum Mol Genet 6:1933-1936] recently reported the synergism between the gene for the K variant of BChE (BCHE-K) and the epsilon4 allele of apolipoprotein E (APOE epsilon4) in late-onset confirmed AD with Caucasian subjects. The authors found that the allelic frequency of BCHE-K was 0.17 in 74 subjects with late-onset histopathologically diagnosed AD, which was higher than the frequencies in elderly control subjects (0.09) and in other dementias (0.07-0.10). The association of BCHE-K with late-onset AD was limited to carriers of APOE epsilon4, giving odds ratios of confirmed late-onset AD of 6.9-12.8. In the present study, we report the BCHE-K allelic frequencies in late-onset AD cases and in age-matched controls of the Korean population, which were 0.22 and 0.17, respectively. We could not find any association between BCHE-K and AD regardless of APOE epsilon4 carrier status. However, APOE epsilon4 clearly showed higher frequency in AD (0.33) than in elderly controls (0.09), giving an odds ratio of 5.2 (95% confidence interval, 2.7-10.0). Our results do not support the conclusion that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE epsilon4 as a susceptibility gene for late-onset AD, at least in the Korean population.
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PMID:No association between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset Alzheimer's disease. 1020 26

This paper reviews available and potential treatments for the cognitive disturbances associated with Alzheimer's disease. The neurochemical, neuropathological, and molecular-biological abnormalities associated with this disorder, as well as possible sites for pharmacological intervention, are discussed. These sites include genetic alterations in apolipoprotein E, amyloid precursor protein, and presenilin. Additionally, modification of amyloid processing, tau processing, and calcium regulation may have a role in future treatment. Intriguing epidemiological findings involving antiinflammatories, antioxidants, and estrogen for the cognitive deficits associated with Alzheimer's disease suggest the need for clinical trials of these agents. The current status of cholinesterase inhibitors, muscarinic receptor agonists, nicotine, and adrenergic and glutaminergic approaches to treatment are described.
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PMID:Experimental approaches to cognitive disturbance in Alzheimer's disease. 1037 Apr 29

Impairments in cholinergic neurotransmitter systems of the basal forebrain are a hallmark of Alzheimer's disease pathophysiology. The presence of the epsilon4 allele of apolipoprotein E was recently implicated as a major risk factor in both familial and sporadic Alzheimer's disease. The present study examined the integrity of cholinergic and non-cholinergic systems in apolipoprotein E-deficient, memory-impaired mice. Choline acetyltransferase activity, hippocampal acetylcholine release, nicotinic and muscarinic (M1 and M2) receptor binding sites and acetylcholinesterase cell or terminal density showed no signs of alteration in either three-month or 9.5-month-old apolipoprotein E-deficient mice compared to controls. In contrast, long-term potentiation was found to be markedly reduced in these mice, but increases in the strength of stimulation induced the same level of long-term potentiation as that observed in controls. These alterations did not appear to be the consequence of modifications in the binding properties of glutamatergic receptors (N-methyl-D-aspartate and [RS]-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) but from defective regulation of the (RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid receptor by phospholipase A2 activity. These results support the notion that apolipoprotein E plays a fundamental role in neuronal plasticity, which could in turn affect cognitive performance through imbalances in extra- and intracellular lipid homeostasis.
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PMID:Cholinergic systems and long-term potentiation in memory-impaired apolipoprotein E-deficient mice. 1042 83

An understanding of the basic pathophysiology and molecular mechanisms of Alzheimer's disease is essential to effective treatment of the disease. Despite multiple hypotheses related to the development and progression of Alzheimer's disease, no unifying theory is currently available. Inflammation, oxidation stress, estrogen hormone status, pathways for production of beta-amyloid42, apolipoprotein E state, cholinergic neuron depletion, and head injury are all possible contributors and therefore provide points of intervention or potential intervention in the development and progression of Alzheimer's disease. Thus, this article reviews current therapeutic modalities, including estrogen replacement therapy, Ginkgo biloba, and the two cholinesterase inhibitors approved in the United States, tacrine and donepezil.
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PMID:Treatment options for Alzheimer's disease. 1073 May 6

The varepsilon4 allele of the apolipoprotein E gene constitutes the major genetic risk factor to develop Alzheimer's disease. If and how this protein contributes to the pathological cascade of Alzheimer's disease is not known. The varepsilon4 allele particularly affects the cholinergic defect, which is one of the most consistent neurotransmitter problems in an Alzheimer's disease brain. We have analysed several parameters of the cholinergic system in brain of apolipoprotein E knockout mice as well as in transgenic mice overexpressing human apolipoprotein E4. We analysed the distribution of cholinergic fibers, the number and morphology of cholinergic neurons and the enzymatic activity of acetylcholinesterase and choline acetyltransferase in different brain regions. Finally, we analysed the distribution and the binding parameters of [3H]hemicholinium-3, a specific marker for the high affinity choline transporter in different brain sections and regions. This extensive effort failed to show any consistent difference in the cholinergic parameters studied, in either the apolipoprotein E4 transgenic mice or in the apolipoprotein E knockout mice, compared to age-matched non-transgenic mice. We conclude that the apolipoprotein E4 is not deleterious per se for the cholinergic system in mouse brain.
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PMID:No evidence for cholinergic problems in apolipoprotein E knockout and apolipoprotein E4 transgenic mice. 1082 23

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.
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PMID:Transgenic mouse models of Alzheimer's disease. 1091 65

A proportion of Alzheimer's disease (AD) patients treated for several months with cholinesterase (ChE) inhibitors have shown some favorable response on cognition, but the characteristics of the responders are still unclear. This study attempts to identify the characteristics of individuals with a positive behavioral response after a double-blind randomized administration of a single oral dose of tacrine (40 mg) and placebo to AD patients. Furthermore, the relationship between single-dose and long-term responders are examined. Twenty-four mildly to very mildly demented AD patients participated in the study. They all fulfilled the diagnosis of probable AD according to NINCDS-ADRDA criteria. Active treatment (tacrine 40 mg) and placebo was administered in random order on 2 consecutive days, and the effects were evaluated within 2 h using neuropsychological tests (assessing visuospatial ability, episodic memory and attention), registration of EEG activity and measurement of red blood cells (RBC) acetylcholinesterase (AChE), ChE activity and concentrations of tacrine and its metabolites in plasma. Results demonstrated significant improvement, tacrine compared to placebo, in measures of attention, but not in episodic memory or visuospatial ability. A single-dose response was therefore defined in terms of improvement in attention. The tacrine plasma concentration (pcTHA) showed a positively skewed distribution (mean +/- SD: 10.5 +/- 11.8, range: 1.0-51.8 ng/ml). There were no significant differences between single-dose responders compared to nonresponders in pcTHA, metabolites of tacrine, inhibition of AChE in RBC, tau levels in CSF, AChE activity in CSF or plasma and demographic variables. However, single-dose responders showed a higher right frontal alpha/theta ratio on EEG and had lower glucose metabolism in the parietal-temporal association cortex at baseline. In addition, the frequency of apolipoprotein E (APOE) epsilon 4 alleles was higher in responders. Interestingly, the single-dose response was related to the long-term response, although not significantly, which probably was due to lack of power. To conclude, the present study identified single-dose responders in terms of improved attentional performance associated with a relatively higher alpha/theta activity in the right frontal regions of the brain measured on EEG and predominance of APOE epsilon 4 allele.
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PMID:Responder characteristics to a single oral dose of cholinesterase inhibitor: a double-blind placebo-controlled study with tacrine in Alzheimer patients. 1112 38


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