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Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele 总被引:5,自引:0,他引:5
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Cook DG Leverenz JB McMillan PJ Kulstad JJ Ericksen S Roth RA Schellenberg GD Jin LW Kovacina KS Craft S 《The American journal of pathology》2003,162(1):313-319
Abeta is the major component of amyloid plaques characterizing Alzheimer's disease (AD). Abeta accumulation can be affected by numerous factors including increased rates of production and/or impaired clearance. Insulin-degrading enzyme (IDE) has been implicated as a candidate enzyme responsible for the degradation and clearance of Abeta in the brain. We have previously shown that AD patients exhibit abnormalities in insulin metabolism that are associated with apoliprotein E (APOE) status. The possible association of IDE with AD, as well as the link between APOE status and insulin metabolism, led us to examine the expression of IDE in AD. We report that hippocampal IDE protein is reduced by approximately 50% in epsilon4+ AD patients compared to epsilon4- patients and controls. The allele-specific decrease of IDE in epsilon4+ AD patients is not associated with neuronal loss since neuron-specific enolase levels were comparable between the AD groups, regardless of APOE status. Hippocampal IDE mRNA levels were also reduced in AD patients with the epsilon4 allele compared to AD and normal subjects without the epsilon4 allele. These findings show that reduced IDE expression is associated with a significant risk factor for AD and suggest that IDE may interact with APOE status to affect Abeta metabolism. 相似文献
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0 引言 人类免疫缺陷病毒 (human immunodeficiencyvirus,HIV) - 1编码的反式激活蛋白 TAT具有独特的跨膜运转方式 ,而且有转导速度快 ,效率高的特点 ,被称为蛋白转导结构域 (protein transduction domain,PTD) [1 ,2 ] .本研究用PCR扩增了慢性粒细胞白血病慢粒 bcr/ abl融合蛋白的基因片段 ,在其 5′端融合 PTD结构域的编码区后在大肠杆菌中进行了表达 .表达产物经纯化后 ,加入培养的 HL 6 0细胞 ,表达的蛋白可直接进入细胞内 .这一结果为用外源蛋白负载(L oading)免疫细胞提供了新的途径 .1 材料和方法1.1 DNA重组 人工合… 相似文献
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D L Garver H Dekirmenjian J M Davis R Casper S Ericksen 《The American journal of psychiatry》1977,134(3):304-307
The authors studied neuroleptic concentration-therapeutic response curves for butaperazine (BPZ), a piperazine phenothiazine, in 10 schizophrenic patients during the first 12 days of treatment. BPZ bound to red blood cells (RBC) was more strongly correlated with therapeutic response than was plasma BPZ. RBC BPZ concentrations could be used to define a "therapeutic window", an optimun concentration for therapeutic response, above and below which favorable response diminishes. The authors emphasize the preliminary nature of the data but suggest that levels of RBC-bound neuroleptic may provide an important guide for dosage regulation in schizophrenic patients. 相似文献
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目的观察小分割分次立体定向放射治疗(fractionated stereotatic radiation therapy,FSRT)脑转移瘤的近期疗效.方法15例病人单纯全脑外照射(WBRT组),中间平面剂量20~40Gy/10~20次/2~4周.17例病人接受FSRT(FSRT组),每次分次剂量为2.5~3.0Gy.其中11病人行单纯FSRT,中心总剂量为30~60Gy/1 0~20次/2~4周;6例病人先行WBRT,然后行FSRT,中心总剂量为46~60Gy/5~6周.结果KSP评分增加10分以上者,WBRT组为5 3.3%,FSRT组为82.4%.(P<0.05).WBRT组有效率(CR PR)为50.0%;FSRT组有效率(CR PR)为80.0%.中位生存率:WBRT组为3.5月,FSRT组为10.0月.结论FSRT能有效地控制脑转移瘤,减轻神经系统症状,提高生存质量,延长病人生存期,而没有增加副作用,值得临床推广应用. 相似文献
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Jianguo Liu Spencer S Ericksen Dan Besspiata Charles W Fisher Grazyna D Szklarz 《Drug metabolism and disposition》2003,31(4):412-420
Key residue Val-382 in P450 1A1 has been predicted to interact with the alkoxy chain of resorufin derivatives. Therefore, we undertook a detailed analysis of substrate mobility in the active site of the P450 1A1 homology model and assessed the effect of mutations at position 382. Dynamic trajectories of 7-methoxy-, 7-ethoxy-, and 7-pentoxyresorufin indicated that 7-ethoxyresorufin would be oxidized most efficiently by the wild-type enzyme. The Val-382-->Ala mutation would increase the O-dealkylation of 7-pentoxyresorufin but decrease the oxidation of other substrates. In the case of the V382L mutant, the large bulk of Leu would block alkoxyresorufins from productive binding orientations leading to lowered activities. Binding free energy calculations for three substrates with 1A1 WT and two mutants indicated that binding constants would be similar for all enzyme-substrate combinations. Modeling predictions were tested experimentally. The plasmid containing the cDNA for human P450 1A1 modified for bacterial expression was altered to include a C-terminal PCR-generated six histidine domain to facilitate enzyme purification. The V382A and V382L mutants were constructed by site-directed mutagenesis and Escherichia coli-expressed enzymes purified using Ni-NTA affinity chromatography. The activity of the WT 1A1 was highest toward 7-ethoxyresorufin and lowest toward 7-pentoxyresorufin. Both mutants displayed a decrease in V(max) with 7-methoxy- and 7-ethoxyresorufin, whereas for the V382A mutant, V(max) with 7-pentoxyresorufin was increased. No significant changes in K(m) were observed relative to the wild-type enzyme. The experimental results are thus in good agreement with modeling predictions. 相似文献
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We compared the tumor-initiating activities toward mouse skin of two
structurally related polycyclic aromatic hydrocarbon diol epoxides: racemic
anti-1,2,3,4-tetrahydro-5,6-dimethylchrysene-1,2-diol-3,4- epoxide
(5,6-diMeCDE) and racemic anti-1,2,3,4-tetrahydro-5-
methylchrysene-1,2-diol-3,4-epoxide (5-MeCDE). Tumors induced by these diol
epoxides were analysed for mutations in the Ha-ras gene. 5,6- diMeCDE is
derived from the non-planar parent compound 5,6- dimethylchrysene, and
reacts to approximately equal extents with dA and dG in DNA, whereas
5-MeCDE is derived from a nearly planar parent compound, 5-methylchrysene,
and reacts mainly with dG in DNA. 5,6- diMeCDE, at initiating doses of 33,
100 or 400 nmol per mouse, induced 1.2, 2.2 and 6.2 skin tumors per mouse,
respectively. It was significantly less tumorigenic than 5-MeCDE which
induced 3.1, 7.5 and 9.1 skin tumors per mouse at the same doses. Tumors
induced by 5,6- diMeCDE had a large number of CAA-->CTA mutations in
codon 61 of the Ha- ras gene: 50, 55 and 75% of the tumors analysed had
this mutation at the 33, 100 and 400 nmol doses. No mutations were found in
codons 12 and 13 in the tumors induced by 5,6-diMeCDE. In contrast,
CAA-->CTA mutations in codon 61 were rarely seen in tumors induced by
5-MeCDE. At the highest dose of 5-MeCDE, 20% of the tumors analysed had
mutations at G of codons 12 and 13. The results of this comparative study
support the hypothesis that mutations in the Ha-ras gene in mouse skin
tumors induced by PAH diol epoxides occur as a result of their direct
reaction with the gene. However, pathways other than the commonly observed
Ha- ras codon 61 mutations are clearly important in mouse skin
tumorigenesis by these diol epoxides.
相似文献
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