β淀粉样蛋白致线粒体功能障碍的研究现状

阿尔茨海默病(AD)是痴呆中最常见的一种类型,发病率在85岁以前随年龄增加而增加,几乎每5年增加1倍[1],但病因至今尚未阐明,β淀粉样蛋白(Aβ)在AD发病机制中起着关键的作用,越来越多的证据表明线粒体是Aβ发挥毒性作用的一个重要靶位[2],也有研究揭示了线粒体的功能紊乱与衰老及神经退行性疾病密切相关[3].     

阿尔茨海默病β淀粉样蛋白的研究进展

阿尔茨海默病（AD）即老年痴呆症，是痴呆的最常见类型之一，是一种以记忆能力减退、认知功能障碍、行为异常为特征的脑退行性疾病，AD已成为继心脏病、癌症和中风之后的第4号杀手。近年来，研究发现AD患者大脑中老年斑的主要成分-Aβ可能是该病发病机制中的起始因素和关键环节。     

β淀粉样蛋白在神经血管单元损伤中的作用

β淀粉样蛋白(mlyloid-β,Aβ)沉积是脑淀粉样血管病(cerebral amyloid angiopathy,CAA)和阿尔茨海默病(Alzheimer's disease,AD)的关键病理学基础.目前的研究强调,神经血管单元细胞之间内环境的稳定是维持脑功能正常的关键.本文综述了Aβ与神经血管单元损伤的关系,期望对CAA和AD的临床防治提供一些新的思路.     

β淀粉样蛋白及tau蛋白相关机制在阿尔茨海默病中的研究进展

<正>阿尔茨海默病(AD)又称老年性痴呆,临床上患者表现为精神状态改变,包括记忆、定向、智力、判断能力及情感障碍和行为失常等。女性发病为男性的2倍,患者常在发病后2~8年死于营养不良、支气管肺炎及全身衰竭[1]。本病的病变以额叶、顶叶及颞叶最明显。主要病理变化有:(1)老年斑(SP),为一种细胞外结构,其中心为β淀粉样蛋白(Aβ)。(2)神经纤维缠结(NFT),以磷酸化的微管相关蛋白tau蛋白为主。此变化是     

吲哚美辛对β-淀粉样蛋白诱导脑内炎症损伤的保护作用

目的　建立大鼠Alzheimer病 (AD)炎症病理模型 ,探讨吲哚美辛在AD中的防治作用。　方法　在大鼠双侧海马CA1区定向注射 β 淀粉样蛋白 (Aβ)作为模型组 ,注射生理盐水作为对照组 ,吲哚美辛灌胃治疗模型大鼠 ,以蒸馏水作治疗对照。 2周后各组大鼠均作Y型迷宫测试 ,然后对大鼠海马进行HE、刚果红、尼氏染色及免疫组化检测等病理学观察。采用方差分析对量化指标行统计分析。　结果　吲哚美辛显著抑制Aβ诱导的大鼠海马胶质细胞增生 ,具有白细胞介素 1β(IL 1β)高表达、神经元丧失以及空间学习记忆能力减退等效应 ;检测各组大鼠海马CA1区锥体细胞带损伤长度显示模型组和生理盐水对照组分别为 (1 80 8± 0 2 89)和 (0 378± 0 0 6 2 )mm ,吲哚美辛治疗组和治疗对照组分别为 (0 76 2± 0 15 3)和 (1 82 2± 0 2 78)mm ,(P <0 0 1)。　结论　在体条件下吲哚美辛显著抑制Aβ诱导的海马炎症损伤效应 ,支持AD的抗炎治疗假说     

早老素、β-淀粉样蛋白及神经元突触改变在阿尔茨海默病发生中的相互关系

研究表明阿尔茨海默病 (AD)中枢神经系统病理改变与早老素 (presenilin ,PS)、β 淀粉样蛋白 (Aβ)及神经元突触改变等因素密切相关。本文就PS、Aβ和神经元突触改变在AD发生过程中的相互关系进行阐述。1　PS自从 1992年发现PS 1基因后〔1〕,1995年又确定了PS 2基因〔2〕。PS的mRNA分析显示 ,PS 1和PS 2在神经系统有广泛的表达 ;同样也存在于其他许多器官中〔3〕。PS在人类一般常局限于粒细胞及新皮层等相同的神经组织中。正常人神经细胞与AD患者受损的神经细胞相比 ,PS表达可能相反 ,AD病人神经元纤维缠结 (NFT)中对PS免疫…     

叠氮钠对SH-SY5Y人神经母细胞瘤细胞膜电位和胞内β-淀粉样蛋白表达的影响

目的观察线粒体呼吸链复合体Ⅳ抑制剂叠氮钠对SH-SY5Y细胞的细胞膜电位及胞内β-淀粉样蛋白(Aβ)表达水平的影响,以探讨用叠氮钠建立模拟Alzheimer病(AD)脑中神经细胞能量代谢障碍的细胞模型的可能性. 方法不同浓度的叠氮钠损伤细胞后,用激光共聚焦显微镜观察细胞膜电位;用免疫细胞化学法检测细胞内β-淀粉样蛋白前体蛋白(APP)和Aβ的表达水平. 结果叠氮钠在浓度25～100 mmol/L时,与细胞共孵育4 h,可使细胞膜电位去极化程度明显增高,并引起胞内Aβ表达显著增高,但对胞内APP表达水平影响不明显. 结论叠氮钠致神经细胞损伤模型可能是模拟AD患者脑中与线粒体复合体Ⅳ损伤相关的病理改变的较好模型.     

去松果体对β-淀粉样蛋白神经毒性的影响

目的 探讨松果体功能减退致褪黑素（ＭＴ）分泌减少对β－淀粉样蛋白（Ａβ）神经毒性的影响及其初步机制。方法 将ＳＤ６周大鼠随机分为２组,实验组摘除松果体,对照组给假手术,２组均在术后４０ｄ给予Ａβ１－４０ １０μｇ右侧海马注射,７ｄ标本用Ｎｉｓｓｌ、ＨＥ、改进甲醇刚果红染色,ＴＵＮＥＬ原位标记方法检测海马神经元病理变化。结果 以图像分析仪测量Ｎｉｓｓｌ染色神经细胞带丢失情况,发现实验组丢失长度「（６     

β淀粉样蛋白寡聚体参与阿尔茨海默病发病机制的研究进展

阿尔茨海默病(AD)是痴呆的最常见病因,我国AD患者群体巨大,AD防治势在必行.淀粉样蛋白斑块靶向治疗的失败让毒性β淀粉样蛋白寡聚体(AβOs)学说愈加醒目,体内、外试验证明AβOs的神经毒性可能是AD病理改变的原因.本文主要阐述AβOs致病机制的最新研究进展和治疗策略,旨在更好地了解AD与AβOs之间的关系,为临床进...     

β淀粉样蛋白与早老素在细胞凋亡中的作用

阿尔茨海默病是一种多因异质性疾病,其发病机制仍在深入研究。业已证实,细胞凋亡在阿尔茨海默病的发病中起重要作用。β淀粉样蛋白及异常的早老素1、2可诱导神经细胞凋亡,从而导致神经元丢失。     

Bioactivation of nitroglycerin by the mitochondrial aldehyde dehydrogenase

The mitochondrial aldehyde dehydrogenase (ALDH2, mtALDH) was recently found to catalyze the reduction of nitroglycerin (glyceryl trinitrate [GTN]) to generate nitrite and 1,2-glyceryl dinitrate. The nitrite generated within the mitochondria is metabolized further to generate nitric oxide (NO)-based bioactivity, by reduction to NO and/or by conversion to S-nitrosothiol, as revealed by a series of biochemical, pharmacologic, and genetic studies. These studies also demonstrated that mechanism-based inactivation of mtALDH is involved in the development of GTN tolerance. In mice in which the mtALDH gene was selectively deleted (mtALDH(-/-)), vascular responsiveness to low but not to high GTN concentrations was eliminated, indicating the existence of an additional mechanism of GTN biotransformation ("high K(m)" pathway). In addition, bioactivation of isosorbide dinitrate/mononitrate vasodilators is independent of mtALDH. Induction of GTN tolerance in vitro in aortae from normal mice selectively affected responsiveness to low doses of GTN, and the remaining responsiveness to high doses of GTN in mtALDH(-/-) vasculature did not exhibit tolerance. These findings suggest strongly that the high K(m) pathway is not involved in the development of GTN tolerance that is mechanism-based. Notably, recent studies indicate that individuals of East Asian origin with the common E487K mutation of mtALDH, which results in decreased mtALDH activity, are significantly less responsive to GTN. These observations in toto provide strong support for the conclusion that mtALDH provides the necessary and sufficient enzymatic mechanism for biotransformation of clinically relevant concentrations of GTN to NO-based vasoactivity and indicate in addition that inactivation of mtALDH plays a significant role in the development of mechanism-based GTN tolerance.     

Time-dependent and ethanol-induced cardiac protection from ischemia mediated by mitochondrial translocation of varepsilonPKC and activation of aldehyde dehydrogenase 2

The cardioprotective effects of moderate alcohol consumption have been well documented in animal models and in humans. Protection afforded against ischemia and reperfusion injury (I/R) proceeds through an ischemic preconditioning-like mechanism involving the activation of epsilon protein kinase C (varepsilonPKC) and is dependent on the time and duration of ethanol treatment. However, the substrates of varepsilonPKC and the molecular mechanisms by which the enzyme protects the heart from oxidative damage induced by I/R are not fully described. Using an open-chest model of acute myocardial infarction in vivo, we find that intraperitoneal injection of ethanol (0.5 g/kg) 60 min prior to (but not 15 min prior to) a 30-minute transient ligation of the left anterior descending coronary artery reduced I/R-mediated injury by 57% (measured as a decrease of creatine phosphokinase release into the blood). Only under cardioprotective conditions, ethanol treatment resulted in the translocation of varepsilonPKC to cardiac mitochondria, where the enzyme bound aldehyde dehydrogenase-2 (ALDH2). ALDH2 is an intra-mitochondrial enzyme involved in the detoxification of toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE) and 4-HNE mediates oxidative damage, at least in part, by covalently modifying and inactivating proteins (by forming 4-HNE adducts). In hearts subjected to I/R after ethanol treatment, the levels of 4-HNE protein adducts were lower and JNK1/2 and ERK1/2 activities were diminished relative to the hearts from rats subjected to I/R in the absence of ethanol. Together, this work provides an insight into the mitochondrial-dependent basis of ethanol-induced and varepsilonPKC-mediated protection from cardiac ischemia, in vivo.     

Time-dependent and ethanol-induced cardiac protection from ischemia mediated by mitochondrial translocation of ?PKC and activation of aldehyde dehydrogenase 2

The cardioprotective effects of moderate alcohol consumption have been well documented in animal models and in humans. Protection afforded against ischemia and reperfusion injury (I/R) proceeds through an ischemic preconditioning-like mechanism involving the activation of epsilon protein kinase C (?PKC) and is dependent on the time and duration of ethanol treatment. However, the substrates of ?PKC and the molecular mechanisms by which the enzyme protects the heart from oxidative damage induced by I/R are not fully described. Using an open-chest model of acute myocardial infarction in vivo, we find that intraperitoneal injection of ethanol (0.5 g/kg) 60 min prior to (but not 15 min prior to) a 30-minute transient ligation of the left anterior descending coronary artery reduced I/R-mediated injury by 57% (measured as a decrease of creatine phosphokinase release into the blood). Only under cardioprotective conditions, ethanol treatment resulted in the translocation of ?PKC to cardiac mitochondria, where the enzyme bound aldehyde dehydrogenase-2 (ALDH2). ALDH2 is an intra-mitochondrial enzyme involved in the detoxification of toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE) and 4-HNE mediates oxidative damage, at least in part, by covalently modifying and inactivating proteins (by forming 4-HNE adducts). In hearts subjected to I/R after ethanol treatment, the levels of 4-HNE protein adducts were lower and JNK1/2 and ERK1/2 activities were diminished relative to the hearts from rats subjected to I/R in the absence of ethanol. Together, this work provides an insight into the mitochondrial-dependent basis of ethanol-induced and ?PKC-mediated protection from cardiac ischemia, in vivo.     

Monoamine metabolism and behavioral responses to ethanol in mitochondrial aldehyde dehydrogenase knockout mice

BACKGROUND: It is widely accepted that, in addition to removing acetaldehyde produced during the metabolism of ethanol, mitochondrial aldehyde dehydrogenase (ALDH2) functions in the pathway by which aldehyde metabolites of the monoamines dopamine (DA) and serotonin (5-HT) are converted to their acidic metabolites. Moreover, studies of ALDH2 inhibitors used for treating alcoholism suggest that their antidipsotropic effects may be related to inhibition of monoamine metabolism. Therefore, we examined the hypothesis that altered brain monoamine metabolism is related to the influence of ALDH2 on behavioral responses to ethanol. METHODS: Mice were generated with a gene-trap mutation of the ALDH2 gene. ALDH2 mRNA was absent in ALDH2-/- mice. Western blot analysis of liver mitochondria confirmed the absence of ALDH2 protein in the ALDH2-/- mice. Wild-type and ALDH2-deficient mice were tested for the effects of different doses of ethanol on locomotor activity, ataxia, and a 2-bottle ethanol-water preference test. RESULTS: Wild-type and ALDH2+/- mice preferred ethanol to water. However, ALDH2-/- mice drank significantly less ethanol than wild-type or ALDH2+/- mice. Locomotor activity and ataxia were significantly more affected by ethanol in ALDH2-/- mice than in wild-type or ALDH2+/- mice. There was no effect of genotype on levels of 5-HT, DA, or their precursors or metabolites in several brain regions, as measured by HPLCec. CONCLUSIONS: The results indicate that: (1) the effect of the mutant genotype on behavioral responses to ethanol is unrelated to altered brain monoamine metabolism and (2) ALDH2 is not required for the metabolism of brain monoamines in vivo.     

Polymorphisms of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 and colorectal cancer risk in Chinese males

AIM： To evaluate the relationship between drinking and polymorphisms of alcohol dehydrogenase 2 （ADH2） and/or aldehyde dehydrogenase 2 （ALDH2） for risk of colorectal cancer （CRC） in Chinese males. METHODS： A case-control study was conducted in 190 cases and 223 population-based controls. ADH2 Arg47His （G-A） and ALDH2 Glu487Lys （G-A）genotypes were identified by PCR and denaturing high-performance liquid chromatography （DHPLC）. Information on smoking and drinking was collected and odds ratio （OR） was estimated. RESULTS= The ADH2 A/A and ALDH2 G/G genotypes showed moderately increased CRC risk. The age- and smoking-adjusted OR for ADH2 A/A relative to G/A and G/G was 1.60 （95% CI=1.08-2.36）, and the adjusted OR forALDH2 G/G relative to G/A and A/A was 1.79 （95% CI= 1.19-2.69）. Significant interactions between ADH2, ALDH2 and drinking were observed. As compared to the subjects with ADH2 G and ALDH2 A alleles, those with ADH2 A/A and ALDH2 G/G genotypes had a significantly increased OR （3.05, 95% CI= 1.67-5.57）. The OR for CRC among drinkers with the ADH2 A/A genotype was increased to 3.44 （95% CI= 1.84-6.42） compared with non-drinkers with the ADH2 G allele. The OR for CRC among drinkers with the ALDH2 G/G genotype was also increased to 2.70 （95% CI= 1.57-4.66） compared with non-drinkers with the ALDH2 A allele. CONCLUSION： Polymorphisms of the ADH2 and ALDH2 genes are significantly associated with CRC risk. There are also significant gene-gene and gene-environment interactions between drinking and ADH2 and ALDH2 polymorphisms regarding CRC risk in Chinese males.     

Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase.

Human mitochondrial aldehyde dehydrogenase (ALDH-I) is potently, reversibly, and selectively inhibited by an isoflavone isolated from Radix puerariae and identified as daidzin, the 7-glucoside of 4',7-dihydroxyisoflavone. Kinetic analysis with formaldehyde as substrate reveals that daidzin inhibits ALDH-I competitively with respect to formaldehyde with a Ki of 40 nM, and uncompetitively with respect to the coenzyme NAD+. The human cytosolic aldehyde dehydrogenase isozyme (ALDH-II) is nearly 3 orders of magnitude less sensitive to daidzin inhibition. Daidzin does not inhibit human class I, II, or III alcohol dehydrogenases, nor does it have any significant effect on biological systems that are known to be affected by other isoflavones. Among more than 40 structurally related compounds surveyed, 12 inhibit ALDH-I, but only prunetin and 5-hydroxydaidzin (genistin) combine high selectivity and potency, although they are 7- to 15-fold less potent than daidzin. Structure-function relationships have established a basis for the design and synthesis of additional ALDH inhibitors that could both be yet more potent and specific.