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1.
Solubilization of beta-amyloid-(1-42)-peptide: reversing the beta-sheet conformation induced by aluminum with silicates. 总被引:1,自引:0,他引:1
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G D Fasman A Perczel C D Moore 《Proceedings of the National Academy of Sciences of the United States of America》1995,92(2):369-371
Plaques are one of the two lesions found in the brain of patients with Alzheimer disease. Using a synthetic peptide corresponding to rat beta-amyloid-(1-42) (beta A4), circular dichroism (CD) analyses were performed to examine the effect of Na4SiO4 on the conformational state produced by Al3+. A previous study on fragments of neuronal proteins involved in tangle formation had shown a conformational transition from a beta-pleated sheet to a soluble random coil upon addition of Na4SiO4. In the present study, CD measurements showed that the beta-pleated sheet conformation of beta A4 induced by Al3+ was reversed to the random coil soluble form by the addition of Na4SiO4. The tight binding of SiO4(4-) with Al3+ provides the mechanism for this transition. These results provide insight into the role of aluminum in the Alzheimer diseased brain and suggests that investigation of the use of silicates as a therapeutic agent. 相似文献
2.
Recognition of tau epitopes by anti-neurofilament antibodies that bind to Alzheimer neurofibrillary tangles. 总被引:10,自引:10,他引:10
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H Ksiezak-Reding D W Dickson P Davies S H Yen 《Proceedings of the National Academy of Sciences of the United States of America》1987,84(10):3410-3414
Eleven anti-neurofilament (anti-NF) monoclonal antibodies were studied for their reactivity with heat-stable, microtubule-associated proteins and Alzheimer neurofibrillary tangles (ANT). On immunoblots of NF proteins, the antibodies recognized epitopes that were variably sensitive to Escherichia coli alkaline phosphatase. Eight of the antibodies showed reactivity with ANT and decreased binding to electroblotted NF after phosphatase treatment. The same eight antibodies reacted with tau proteins from bovine and rat brain, binding to tau proteins was also substantially reduced by phosphatase. Of the eight antibodies that bound to animal tau proteins, five also bound to tau proteins from normal human brain. All of the antibodies that bound to animal tau proteins stained ANT in frozen tissue sections. Brief treatment of tissue sections with trypsin in most cases enhanced antibody binding to ANT. All antibodies that lacked reactivity with tau proteins failed to bind ANT. Phosphatase treatment of Alzheimer tissue sections did not change the immunoreactivity of ANT and neurites in senile plaques with ANT-reactive, anti-NF antibodies, except for two antibodies that showed decreased binding to ANT. In contrast, axonal staining was decreased or eliminated by phosphatase treatment, similar to the response of electroblotted NF and tau proteins. These results suggest that staining of ANT by anti-NF antibodies may be due to cross-reaction of anti-NF with epitopes in tau proteins, the epitopes in axons, NF, and tau are sensitive to the effect of phosphatase, whereas the majority of those in ANT are not, and some of the epitopes in ANT that are shared with NF and tau proteins are not readily accessible to antibody binding. 相似文献
3.
M Clauberg J G Joshi 《Proceedings of the National Academy of Sciences of the United States of America》1993,90(3):1009-1012
The brain of Alzheimer disease patients contains plaques that are diagnostic for the disease. The plaques also contain beta-amyloid peptide, alpha 1-antichymotrypsin, and the element aluminum. We present indirect evidence that can relate all three components of plaques to each other in such a way as to suggest their involvement in the etiology of the disease. The beta-amyloid peptide is derived by proteolytic processing from beta-amyloid precursor proteins and some of these proteins contain a domain that is highly homologous to bovine pancreatic trypsin inhibitor. Bovine pancreatic trypsin inhibitor also inhibits alpha-chymotrypsin and we show that aluminum affects both the activity and the inhibition of this enzyme. At pH 6.5, in the presence of aluminum, the enzyme activity is doubled, and the inhibitor is only 1% as effective as in the absence of the metal ion. The inhibition by BX-9, a protease inhibitor prepared from protein components of amyloid plaques, is also reduced by aluminum; so too is that by alpha 1-antichymotrypsin but to a lesser degree. In the Alzheimer brain, we propose that aluminum may accelerate proteolytic processing of the beta-amyloid precursor protein by suppression of the inhibitor domain. Thus, the beta-amyloid peptide may accumulate and initiate plaque formation. 相似文献
4.
Microtubule-associated protein 2: monoclonal antibodies demonstrate the selective incorporation of certain epitopes into Alzheimer neurofibrillary tangles. 总被引:20,自引:8,他引:20
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K S Kosik L K Duffy M M Dowling C Abraham A McCluskey D J Selkoe 《Proceedings of the National Academy of Sciences of the United States of America》1984,81(24):7941-7945
Neurofibrillary tangles (NFT) are the principal structural alteration of neuronal cell bodies in Alzheimer disease as well as in normal aging of the human brain. While the ultrastructure of these intraneuronal lesions has been extensively studied, the biochemical composition of the fibers comprising the NFT is unknown. We report the production of three monoclonal antibodies against the microtubule-associated protein 2 (MAP-2), one of which intensely labels Alzheimer NFT. All three antibodies specifically recognize MAP-2 on immunoblots and stain brain tissue in a characteristic dendritic pattern. The three antibodies are directed against at least two different antigenic sites on the MAP-2 molecule, and one appears to recognize a phosphorylation site on MAP-2. That only one of the three antibodies immunolabels NFT suggests that the formation of the tangle involves some modification of the MAP-2 molecule. Our findings suggest that one aspect of Alzheimer-type neurofibrillary pathology is an aggregation of MAP-2 or MAP-2 fragments with altered neurofilamentous elements present in NFT. Normal interactive function, which putatively occurs between neurofilaments and MAP-2, may thus be disrupted in Alzheimer disease. 相似文献
5.
Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau) 总被引:24,自引:22,他引:24
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J G Wood S S Mirra N J Pollock L I Binder 《Proceedings of the National Academy of Sciences of the United States of America》1986,83(11):4040-4043
The relationship of the neurofibrillary tangle, found in Alzheimer disease and aged brains, to normal or abnormal cytoskeletal proteins remains elusive. Although immunohistochemical studies have yielded disparate results, most antigenic determinants localized to neurofibrillary tangles are cytoskeletal constituents normally present in neuronal perikarya or dendrites. We report light and electron microscopic immunolabeling of neurofibrillary tangles by a monoclonal antibody to the microtubule-associated protein tau (tau). Dephosphorylation of tissue slices not only increased the number of tau-positive tangles but also produced marked positive immunoreactivity of neuritic plaques. The localization of tau, an axonal protein, to neurofibrillary tangles in the perikaryon in particular suggests that abnormal synthesis, modification, or aggregation of tau may induce aberrant cytoskeletal--cell organelle interactions, subsequent interference with axonal flow, and resultant tangle formation. 相似文献
6.
An antiserum to the N-terminal subsequence of the Alzheimer amyloid beta protein does not react with neurofibrillary tangles 总被引:1,自引:0,他引:1
Polyclonal antibodies were raised against a synthetic peptide corresponding to a subsequence for the first 10 residues of the beta amyloid protein A4 (1-10 beta PA4). In an immunoperoxidase study of Alzheimer brain tissue, these antibodies immunostained senile plaque cores, amyloid vessel walls, and amyloid fibrils surrounding senile plaques and angiopathic vessels. Neurofibrillary tangles stained with thioflavin S or immunostained with anti-Tau immune serum were never immunodetected with the anti 1-10 beta PA4. We confirm that the neurofibrillary tangles do not contain epitopes corresponding to the first 10 residues of the beta PA4. 相似文献
7.
Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. 总被引:15,自引:6,他引:9
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N Arispe E Rojas H B Pollard 《Proceedings of the National Academy of Sciences of the United States of America》1993,90(2):567-571
Amyloid beta protein (A beta P) is the 40- to 42-residue polypeptide implicated in the pathogenesis of Alzheimer disease. We have incorporated this peptide into phosphatidylserine liposomes and then fused the liposomes with a planar bilayer. When incorporated into bilayers the A beta P forms channels, which generate linear current-voltage relationships in symmetrical solutions. A permeability ratio, PK/PCl, of 11 for the open A beta P channel was estimated from the reversal potential of the channel current in asymmetrical KCl solutions. The permeability sequence for different cations, estimated from the reversal potential of the A beta P-channel current for each system of asymmetrical solutions, is Pcs > PLi > PCa > or = PK > PNa. A beta P-channel current (either CS+ or Ca2+ as charge carriers) is blocked reversibly by tromethamine (millimolar range) and irreversibly by Al3+ (micromolar range). The inhibition of the A beta P-channel current by these two substances depends on transmembrane potential, suggesting that the mechanism of blockade involves direct interaction between tromethamine (or Al3+) and sites within the A beta P channel. Hitherto, A beta P has been presumed to be neurotoxic. On the basis of the present data we suggest that the channel activity of the polypeptide may be responsible for some or all of its neurotoxic effects. We further propose that a useful strategy for drug discovery for treatment of Alzheimer disease may include screening compounds for their ability to block or otherwise modify A beta P channels. 相似文献
8.
In several countries it has been observed that there has been no further increase in the prevalence of asthma. This study aimed to look at asthma prevalence in children during the past 15-30 years in The Netherlands. Both general practice registration (Continuous Morbidity Registration, Nijmegen) and surveys of the public health service in Limburg (Southern parts of the Netherlands) were used for this purpose. The general practice registration showed that after a five-fold increase in asthma prevalence during the 1980s and 1990s a downward trend seemed to occur around the turn of the century. The public health service confirms a clear decrease in wheezing and dyspnoea in children during the late 1990s. Thus far, there has been no satisfactory explanation for this observation. 相似文献
9.
Protective anti-Helicobacter immunity is induced with aluminum hydroxide or complete Freund's adjuvant by systemic immunization. 总被引:10,自引:0,他引:10
J M Gottwein T G Blanchard O S Targoni J C Eisenberg B M Zagorski R W Redline J G Nedrud M Tary-Lehmann P V Lehmann S J Czinn 《The Journal of infectious diseases》2001,184(3):308-314
To determine whether systemic immunization against Helicobacter pylori could be achieved with an adjuvant approved for human use, the efficacy of vaccination with Helicobacter antigen in combination with aluminum hydroxide (AlOH) was evaluated in a murine model of Helicobacter infection. Immunization with antigen and AlOH induced interleukin-5-secreting, antigen-specific T cells, and immunization with antigen and complete Freund's adjuvant induced interferon-gamma-secreting, antigen-specific T cells, as determined by ELISPOT assay. Both immune responses conferred protection after challenge with either H. pylori or H. felis, as confirmed by the complete absence of any bacteria, as assessed by both histology and culture of gastric biopsy samples. Protection was antibody independent, as demonstrated with antibody-deficient muMT mice (immunoglobulin-gene knockout mice), and CD4(+) spleen T cells from immunized mice were sufficient to transfer protective immunity to otherwise immunodeficient rag1(-/-) recipients. These results suggest an alternative and potentially more expeditious strategy for development of a human-use H. pylori vaccine. 相似文献
10.
A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. 总被引:33,自引:2,他引:31
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K Hensley J M Carney M P Mattson M Aksenova M Harris J F Wu R A Floyd D A Butterfield 《Proceedings of the National Academy of Sciences of the United States of America》1994,91(8):3270-3274
beta-Amyloid is a 39- to 43-amino-acid neurotoxic peptide that aggregates to form the core of Alzheimer disease-associated senile (amyloid) plaques. No satisfactory hypothesis has yet been proposed to explain the mechanism of beta-amyloid aggregation and toxicity. We present mass spectrometric and electron paramagnetic resonance spin trapping evidence that beta-amyloid, in aqueous solution, fragments and generates free radical peptides. beta-Amyloid fragments, at concentrations that previously have been shown to be neurotoxic to cultured neurons, can inactivate oxidation-sensitive glutamine synthetase and creatine kinase enzymes. Also, salicylate hydroxylation assays indicate that reactive oxygen species are generated by the beta-amyloid-(25-35) fragment during cell-free incubation. These results are formulated into a free radical-based unifying hypothesis for neurotoxicity of beta-amyloid and are discussed with reference to membrane molecular alterations in Alzheimer disease. 相似文献
11.
P Bioulac-Sage L Dubuisson C Bedin P Gonzalez E de Tinguy-Moreaud H Garcin C Balabaud 《Hepatology (Baltimore, Md.)》1992,16(2):418-425
Weaned male rats were fed a 4 ppm selenium diet. Compared after 2 mo with a control group fed a 0.4 ppm diet, the rats' body weights had not significantly decreased and liver function was normal, but portal pressure was 1.8 times higher (p less than 0.05). Liver weight was slightly increased (10.3%; p less than 0.05). All livers had an abnormal appearance. In the less severe cases the surface was only slightly irregular, but in the more severe cases, atrophic micronodular lobes and hypertrophic lobes, with mildly irregular surfaces, were present. On light microscopy, atrophic lobes displayed a peripheral nodular zone with micronodules separated by rows of atrophic hepatocytes without fibrosis, characteristic of nodular regenerative hyperplasia, and a central atrophic zone that was sometimes peliotic. Hypertrophic lobes and livers in the less severe cases had only minor and relatively localized evidence of nodular regenerative hyperplasia; occasional peliosis was seen. In all cases portal veins, hepatic veins and hepatic arteries were normal. By electron microscopy, in nonnodular zones with no obvious evidence of parenchymal atrophy, the endothelial wall showed signs of complete or incomplete capillarization with frequent enlargement of the Disse space. The selenium-enriched diet is a reproducible model of liver nodular regenerative hyperplasia. In this model, damage to the sinusoidal wall could represent the primum movens of microcirculatory disturbances. 相似文献
12.
The binding conformation of Taxol in beta-tubulin: a model based on electron crystallographic density
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Snyder JP Nettles JH Cornett B Downing KH Nogales E 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(9):5312-5316
The chemotherapeutic drug Taxol is known to interact within a specific site on beta-tubulin. Although the general location of the site has been defined by photoaffinity labeling and electron crystallography, the original data were insufficient to make an absolute determination of the bound conformation. We have now correlated the crystallographic density with analysis of Taxol conformations and have found the unique solution to be a T-shaped Taxol structure. This T-shaped or butterfly structure is optimized within the beta-tubulin site and exhibits functional similarity to a portion of the B9-B10 loop in the alpha-tubulin subunit. The model provides structural rationalization for a sizeable body of Taxol structure-activity relationship data, including binding affinity, photoaffinity labeling, and acquired mutation in human cancer cells. 相似文献
13.
A rodent model for Wilms tumors: embryonal kidney neoplasms induced by N-nitroso-N''-methylurea. 总被引:2,自引:1,他引:1
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P M Sharma M Bowman B F Yu S Sukumar 《Proceedings of the National Academy of Sciences of the United States of America》1994,91(21):9931-9935
Embryonal kidney cell tumors develop in rats given the alkylating agent N-nitroso-N'-methylurea as neonates. These tumors resemble the childhood Wilms tumors in their histopathology. Deletions and mutations in the Wilms tumor suppressor gene, WT1, are present in up to 6% of childhood nephroblastomas. To investigate the role of WT1 in rat kidney tumorigenesis, we studied the genetic alterations in WT1 and its target genes. Point mutations were found in WT1 cDNA in 7 of 18 kidney tumors. Mesenchymal tumors contained G-->A transition mutations in codons 128, 364, and 372, typical of the methylating action of N-nitroso-N'-methylurea on DNA. Each of the four nephroblastomas contained the same T-->A mutation at codon 111 of WT1, reflective of transversion mutagenesis by N-nitroso-N'-methylurea in vivo. Like Wilms tumors, mRNA levels of WT1, IGF2, Pax-2, and MK genes were higher than newborn kidney in the majority of the tumors. The histopathology of the rat kidney tumors and the genetic alterations are reminiscent of those observed in Wilms tumors, establishing this as a relevant model system for the human disease. 相似文献
14.
15.
羟基积雪草甙对慢性铝中毒痴呆小鼠的治疗作用 总被引:4,自引:1,他引:3
目的研究羟基积雪草甙(madecassoside,MC)对慢性铝中毒痴呆小鼠的保护作用。方法葡萄糖酸铝按铝400 mg.kg-1.d-1灌胃90 d建立慢性铝中毒痴呆小鼠模型。通过HE染色、Morris水迷宫试验和生化实验,观察MC三种剂量(30、60和120 mg.kg-1.d-1)同步给药90d对小鼠海马神经元损伤、空间学习记忆能力和脑组织单胺氧化酶B(MAO-B)活性的影响。结果与模型组比较,30和60 mg.kg-1.d-1MC明显减轻铝过负荷所致的海马神经元损伤,明显缩短小鼠寻找平台潜伏期(s)(35.9±10.9 vs 16.5±8.4和19.6±10.5)(P<0.05);同时三种剂量MC均明显降低小鼠脑组织中MAO-B活性(U.h-1.mg-1prot)(18.9±1.8 vs 14.6±1.7,13.7±2.3和13.6±1.4)(P<0.05)。结论MC对慢性铝中毒小鼠海马神经元有保护作用,改善痴呆小鼠学习记忆能力。 相似文献
16.
Sérgio L Dalmora Maximiliano S Sangoi Micheli Wrasse Raquel M Bernardi Ricardo M Ferretto Marcio Fronza 《Blood coagulation & fibrinolysis》2008,19(3):254-257
The effects of etoricoxib on blood coagulation parameters were evaluated, along with acetylsalicylic acid, in male Wistar rats. Blood samples were collected at the end of the first, second, third and fourth weeks of the administration period and the plasma concentrations of etoricoxib determined by liquid chromatography-tandem mass spectrometry; the samples were also used for the analysis of the hematological parameters. There were no significant changes in the platelet count and fibrinogen levels, and a decrease by 1.9% of the prothrombin time was detected at the third week. The activated partial thromboplastin time assay showed a nonsignificant shortening. The antiactivated factor X and antiactivated factor II activities showed reductions lower than 2.8 and 1.3%, respectively. These findings and the comparison with acetylsalicylic acid can be helpful to support the benefit-to-risk profile, contributing to the safe therapeutic use. 相似文献
17.
弓形虫致生殖毒性动物模型的建立 总被引:2,自引:0,他引:2
目的通过不同方式用弓形虫速殖子感染BALB/c雌鼠以建立最适宜的生殖毒性小鼠模型。方法将BALB/c雌鼠随机分为正常对照A组、染虫B1-B5组和C1-C5组,每组10只,经腹腔注射,A组注射无菌PBS0.2ml/只,B1-B5组依次每只注射经胰酶消化的弓形虫速殖子25、50、100、200、400个,C1-C5组依次每只注射不经胰酶消化的弓形虫速殖子25、50、100、200、400个,注射体积均为0.2m1,观察小鼠生存状态20d。结果对生存时间用SPSS13.0进行方差分析:染虫组与对照组比较,B1、B2组与对照组比较差异无统计学意义(P〉0.05),B3-B5,C1-C5组与对照组相比差异有统计学意义(P〈0.05);相同剂量的染虫组B、C组间比较,B组生存天数高于C组,差异有统计学意义(P〈0.01);B组和C组内比较,B组组内差异明显,有统计学意义(P〈0.05);C组组内比较差异不明显,无统计学意义(P〉0.05)。结论弓形虫感染BALB/c雌鼠的生殖毒性试验,采用B组即腹腔注射经胰酶消化的弓形虫速殖子最佳。 相似文献
18.
L Beadling L I Rothfield 《Proceedings of the National Academy of Sciences of the United States of America》1978,75(8):3669-3672
Fluorescence techniques were used to study conformational changes in UDPgalactose:lipopolysaccharide alpha,3-galactosyltransferase (EC 2.4.1.44). Intramolecular energy transfer was measured from the single tryptophan residue in the peptide to a pyridoxal phosphate group linked to the same peptide via a reduced Schiff''s base. Significant differences in energy transfer were seen when the enzyme was studied in aqueous solution and after entry into a phospholipid-lipopolysaccharide matrix, paralleling the restoration of its catalytic activity. Further differences were seen when the structures of the phospholipids and lipopolysaccharides were changed. Application of the Förster theory indicated that the changes in energy transfer resulted from changes in distances between the chromophores and/or changes in their relative orientations. The results suggest that entry of this membrane protein into a lipid matrix induces a change in conformation of the protein and that other alternative conformations can be induced by further changes in its lipid environment. 相似文献
19.
Methodologic aspects of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine.
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N H Holford K E Peace 《Proceedings of the National Academy of Sciences of the United States of America》1992,89(23):11466-11470
Tacrine is a cholinesterase inhibitor with activity in the central nervous system originally marketed for the reversal of competitive neuromuscular blockade. Because a marked reduction in cholinergic neurons is a hallmark of brain changes in Alzheimer disease, tacrine has been studied in two placebo-controlled clinical trials of patients with probable Alzheimer disease. Standard analysis of variance (ANOVA) and analysis of covariance (ANCOVA) have shown a difference between the tacrine group and the placebo group in terms of the cognitive component of the Alzheimer disease assessment scale at the end of the placebo-controlled phase. Due to limitations of ANOVA and ANCOVA, only a selected group of patients could be analyzed by those methods. A population pharmacodynamic model has been developed that allows the use of all observations from one or more trials to be combined. It can incorporate any sequence of active or placebo treatments and account for carryover effects of both placebo and active drug. The time courses of active or placebo treatment response and the development of tolerance to active drug or placebo can be defined. The model describes disease progression without treatment, the placebo effect, and the effect of tacrine as a function of daily dose. Placebo effect and active drug effects are modeled by effect site concentration components. 相似文献
20.
Evidence for interference with the intestinal absorption of levothyroxine sodium by aluminum hydroxide. 总被引:2,自引:0,他引:2
A patient with hypothyroidism who was euthyroid on a fixed-dosage, long-term maintenance regimen of levothyroxine sodium developed persistently elevated serum thyrotropin levels while receiving an aluminum hydroxide-containing antacid. The thyrotropin levels returned to normal shortly after cessation of the antacid therapy. These observations indicate that aluminum hydroxide may interfere with the bioavailability of thyroxine. The thyroid function of patients who are receiving replacement or suppressive thyroxine therapy should be monitored following the commencement of concurrent treatment with medications containing aluminum hydroxide. 相似文献