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21.
Objective To evaluate the association of 2616c/T polymorphism in iron regulatory protein 2(IRP2)gene with Alzheimer disease(AD)and Vascular dementia(VD).Methods In this study,281 patients with AD,60 with VD,and 285 normal aged were recruited.The 2616C/T polymorphism in IRP2 gene was analyzed by using polymerase chain reaction-restriction fragment length polymorphism.And the cognitive function was assessed with the Mini-Mental State Examination(MMSE).Results (1)No significant difieFences were demonstrated in IRP2 genotype or allele frequencies between AD patients and controls(χ2=2.46,P=0.292;χ2=2.17,P=0.141 respectively).However,when AD patients were stratified by disease severity.the frequency of T allele carriers in the moderate to severe AD patients was 78.0%,significantly higher than that in controls(69.8%;χ2=4.106,P<0.05).Logistic regression analysis demonstrated that the age-,sex-and ApoE-adiusted OR of modcrate to severe AD patient with T allele was 1.62(95% CI=1.03-2.54).The frequency of T allele carriers or T allele in VD patients was higher than that of controls,but the difference was not statistically significant(P>0.05).(2)The frequency of tit genotype or T allele in the moderate to severe AD patients was significantly higher than that in mild AD patients(25.8%vs.12.5%,χ2=5.477,P<0.05;51.9%vs.40.3%,χ2=5.803,P<0.05 respectively).(3)MMSE scores of the AD patients with TT genotype was significantly lower than ones with CC or CT genotype(P=0.028;P=0.014 respectively).Conclusion The 2616C/T polymorphism in the IRP2 gene is possibly associated with moderate to severe AD.but not associated with VD.And the TT genotype may be a risk factor for cognitive impairment of patients with AD in Chinese Han. 相似文献
22.
We have used quantitative light microscopic autoradiographic techniques to analyze changes in muscarinic cholinergic receptors in the hippocampus in Alzheimer type dementia (ATD). The density and distribution of muscarinic cholinergic receptors has been correlated with the density of neurons, neuritic plaques and neurofibrillary tangles in the CA1 subfield of the hippocampus of control and ATD patients. The number of pyramidal cells per mm2 in the CA1 sector was significantly decreased in ATD cases as compared to controls, although there were large variations among cases. The most marked reductions in cell counts were observed in patients with a history of profound dementia. The densities of muscarinic receptors, as well as the proportions of M1 and M2 subtypes, in the CA1 sector and dentate gyrus were not significantly different between ATD and old non-demented patients. Neuritic plaques, even in high numbers, did not affect the density of muscarinic receptors; moreover, the densities of receptors over the neuritic plaques did not differ from the surrounding neuropil. However, in some ATD cases there was a marked decrease in the concentration of these receptors in the CA1 sector and subiculum, with no change in the proportions of muscarinic receptor subtypes. These patients exhibited frequent extracellular remnants of neurofibrillary tangles (ghost tangles), but scarce neuritic plaques, and were those showing severe losses of pyramidal cells. There was a significant positive correlation between the total concentration of muscarinic receptors in the CA1 and the density of pyramidal cells, suggesting that decreases in receptor concentration result from a severe neuronal loss. We observed that the ratio of muscarinic receptors per pyramidal cell was significantly increased in ATD patients. This might indicate a possible upregulatory mechanism for muscarinic receptors in the population of remaining neurons in ATD. However, decreases of receptor numbers following severe neuronal fall out suggest that compensatory mechanisms are no longer possible in such cases. The question is raised whether these differences between cases reflect different diseases or different stages of the same disease. 相似文献
23.
Histological, immunohistochemical, and electron microscopic evidence of an extracellular, or ghost Pick body has been found in the granular cell layer and, rarely, in the pyramidal cell layer of the hippocampus of an autopsy case of Pick's disease. The ghost Pick body appeared as a blurred, weak argyrophilic mass in the neuropil, and it was composed of accumulated fibrillary structures, 13 nm in diameter, intermingled with glial filament bundles. These ghost Pick bodies did not react with anti-tau and antiubiquitin antibodies, but did react weakly with antiglial fibrillary acidic protein antibody, whereas intracytoplasmic Pick bodies were strongly immunolabeled with anti-tau but only weakly with anti-ubiquitin anti-bodies. These results suggest that the Pick body is discharged into the neuropil after destruction of the mother neuron, loses its immunoreactivity to certain tau and ubiquitin antibodies during this process (thereby inducing a glial reaction) and remains in the neuropil as a ghost Pick body. 相似文献
24.
The heat shock/oxidative stress connection 总被引:2,自引:0,他引:2
M. A. Pappolla M. Sos R. A. Omar K. Sambamurti 《Journal of molecular neuroscience : MN》1996,28(1-3):21-34
Involvement of free-radical oxidations in the aging process has been a topic of interest since Harman's original contribution.
Because of the close association between aging and Alzheimer disease (AD) and the qualitative similarity in the neuropathology
of both conditions, it has been proposed by many investigators that oxidative stress may be important in AD. If such modality
of injury was indeed involved, one should expect to find markers of oxidation and heat shock (since free radicals are key
mediators of heat-shock induction) in brains of patients with AD. In fact, several studies documented abnormal expression
of antioxidant enzymes and heat-shock proteins (HSP) along with other markers of oxidation in AD brains. We showed that abnormally
expressed antioxidant enzymes are topographically associated with senile plaques and neurofibrillary tangles, and that the
activity of these enzymes is (contrary to what one would expect) markedly reduced. These findings have recently been confirmed
by other investigators. Despite a large amount of evidence that suggests an association between oxidative stress and the pathogenesis
of AD, it is not yet known whether oxidative stress is a cause or consequence of the disorder. Future research efforts regarding
the oxidative stress hypothesis of AD should include attempts, at generating AD pathology by oxidative means in laboratory
animals, determining the role and integrity of the heat-shock response in AD, as well as that of various antioxidant systems,
growth factors, and hormones with antioxidant and neuroprotective properties. 相似文献
25.
轻度认知障碍及阿尔茨海默病患者外周血淋巴细胞中蛋白磷酸酯酶-2A的改变 总被引:1,自引:1,他引:0
目的 探讨轻度认知功能障碍(MCI)及阿尔茨海默病(AD)患者外周血淋巴细胞蛋白磷酸酯酶-2A(PP-2A)的变化.方法 用放射性配体结合试验检测11名健康对照者、11例MCI患者及11例AD患者外周血淋巴细胞PP-2A的活性,并用Western bolt检测PP-2A蛋白的表达.结果 MCI组外周血淋巴细胞PP-2A活性(0.71±0.12)及蛋白表达(0.80±0.05)与健康对照组[分别为(1.01±0.09)和(0.96±0.07)]相比明显降低(均P<0.01);AD组PP-2A活性(0.64±0.11)及蛋白表达(0.76±0.06)亦明显降低,与对照组相比差异有统计学意义(均P<0.01);AD组PP-2A活性及蛋白表达比MCI组有降低的趋势,但差异无统计学意义.结论 MCI及AD患者外周血淋巴细胞PP-2A的活性及表达降低,在MCI的诊断中可能有参考价值,同时亦可能对AD的诊断有一定的潜在的意义. 相似文献
26.
P. P. De Deyn V. Van de Velde PhD W. Verslegers J. Saerens B. A. Pickut B. Clincke R. Woestenborghs A. Van Peer 《European journal of clinical pharmacology》1992,43(6):661-662
Summary The single- and repeated-dose pharmacokinetics of sabeluzole have been determined in six elderly patients with [senile] dementia of the Alzheimer type.After a single oral dose of 10 mg sabeluzole, the peak plasma concentration was attained at 1 to 4 h; it averaged 42 ng·ml–1. On repeated dosing (10 mg b. d.), steady-state was virtually attained after 3 days of treatment. Steadystate mean trough and peak plasma concentrations fluctuated between 53 and 94 ng·ml–1. The mean terminal half-life after a single dose and at steady-state was of the order of 33 h.Sabeluzole was well tolerated and at the end of treatment, no systematic changes in blood haematology, biochemistry or urinalysis were seen. 相似文献
27.
P. Schubert T. Ogata S. Ferroni A. McRae Y. Nakamura K. Rudolphi 《Journal of molecular neuroscience : MN》1996,28(1-3):185-190
In view of the increasing evidence that a pathological glial activation plays a significant role in the development of neurodegenerative
diseases, we investigated the underlying molecular signaling as a possible target for a pharmacological therapy. Here, we
are particularly focusing on the endogenous modulation of the Ca2+ and cyclic nucleotide-dependent signaling by the nucleoside adenosine and its reinforcement by the xanthine derivative propentofylline
(PPF). As an experimental model, we used cultured rat microglial cells and astrocytes that are immature, show a high proliferation
rate, and resemble in several aspects pathologically activated glial cells. A prolonged increase of the cellular cAMP level
favored the differentiation of cultured astrocytes and associated properties required for the physiological nerve cell function.
On the other hand, a strengthening of the cyclic nucleotide-dependent signaling inhibited potentially neurotoxic properties
of cultured microglial cells. Similar effects were obtained by treatment with propentofylline, which mimicked modulatory adenosine
effects and increased the intracellular level of cAMP and cGMP. Such a pharmacological glial cell conditioning, obtained by
modifying the strength and the timing of these second messengers, may provide a therapy of neurodegenerative diseases in which
a pathological activation of microglial cells and astrocytes is discussed to play a pathogenic role. 相似文献
28.
Steffen Roiner Nikolas Bakinde Ulrike Zeitschel Reinhard Schliebs Volker Bigl 《International journal of developmental neuroscience》1998,16(7-8):669-673
The present study was conducted to test the hypothesis that cholinergic basalforebrain neurons are a major source of cerebrospinal fluid (CSF) cholinesterases. To address thisquestion enzyme activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inboth CSF and parietal cortex were assayed following selective lesion of basal forebrain cholinergicneurons by a single intracerebroventricular application of the cholinergic immunotoxin192IgG-saporin. Cholinergic immunolesions led to a dramatic decrease in total AChE activity inparietal cortex, which was due to the specific loss of the G4 molecular form while the activity ofthe G1 form was increased as compared to nonlesioned animals. In contrast, the total enzymeactivity of BChE and its molecular forms were not affected by cholinergic lesion in both parietalcortex and CSF. The data suggest, that cholinergic basal forebrain neurons are seemingly not amajor source of cholinesterases in the CSF, and do not provide any evidence for using CSFcholinesterases as a diagnostic marker of basal forebrain cholinergic cell loss in humans. 相似文献
29.
Contribution of redox-active iron and copper to oxidative damage in Alzheimer disease 总被引:1,自引:0,他引:1
Castellani RJ Honda K Zhu X Cash AD Nunomura A Perry G Smith MA 《Ageing research reviews》2004,3(3):319-326
Metal-catalyzed hydroxyl radicals are potent mediators of cellular injury, affecting every category of macromolecule, and are central to the oxidative injury hypothesis of Alzheimer disease (AD) pathogenesis. Studies on redox-competent copper and iron indicate that redox activity in AD resides exclusively within the neuronal cytosol and that chelation with deferoxamine, DTPA, or, more recently, iodochlorhydroxyquin, removes this activity. We have also found that while proteins that accumulate in AD possess metal-binding sites, metal-associated cellular redox activity is primarily dependent on metals associated with nucleic acid, specifically cytoplasmic RNA. These findings indicate aberrations in iron homeostasis that, we suspect, arise primarily from heme, since heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in AD, and mitochondria, since mitochondria turnover, mitochondrial DNA, and cytochrome C oxidative activity are all increased in AD. These findings, as well as studies demonstrating a reduction in microtubule density in AD neurons, suggest that mitochondrial dysfunction, acting in concert with cytoskeletal pathology, serves to increase redox-active heavy metals and initiates a cascade of abnormal events culminating in AD pathology. 相似文献
30.
目的:研究TA9902引起Aβ1-42二级结构变化,了解其抑制Aβ聚集和纤维形成的机制。 方法: 用傅里叶变换红外光谱法(FT-IR)曲线拟合定量分析和特征频谱分析Aβ老化后及TA9902干预后二级结构的变化。 结果: 1 700-1 600 cm-1之间的酰胺I带分析,Aβ1-42单独孵育30 min时,β-折叠片为46.53%;Aβ1-42老化72 h,β-折叠片为65.13%,β-折叠片增加了19.4%。TA9902与Aβ1-42作用β-折叠片为29.04%;与Aβ1-42老化72 h相比,TA9902的存在明显减少β折叠片的含量(下降了36.09%),β-转角的含量明显升高(升高57.56%),α-螺旋也略有升高(2.93%)。呈现出明显的β折叠片向β-转角的转化。其它基团特征峰位显示,TA9902中有酮类尤其是饱和链状酮或α-二酮和烷烃类的-CH2和-CH参与了Aβ1-42的分子变构。 结论: TA9902明显抑制Aβ1-42β-折叠的形成,同时也使Aβ1-42肽的侧链基团发生了化学修饰,提示Aβ的聚集和纤维形成与其分子β-折叠的形成和侧链基团发生了化学修饰有关。 相似文献