黄芪多糖对阿尔茨海默病大鼠神经细胞活性、认知功能及Caspase-9表达水平的影响

目的 探讨黄芪多糖(Astragalus polysacharin,APS)对阿尔茨海默病(Alzheimer’s disease,AD)大鼠神经细胞活性、认知功能及天冬氨酸特异性半胱氨酸蛋白酶(Cysteinyl aspartate specific protease,Caspase)-9表达水平的影响。方法 36只无特定病原体(Specific pathogen free, SPF)级美国斯泼累格·多雷(Sprague Dawley)雌雄各半的大鼠,按照随机数字表分为6组,正常组、AD组、药物对照组、干预A组、干预B组及干预C组; 除正常组外,其余大鼠建立AD大鼠模型; 建模后药物对照组采用0.5 g/kg的吡拉西坦灌胃,干预A组、干预B组及干预C祖均采用0.2、0.4及0.8 g/kg的黄芪多糖(Astragalus polysacharin,APS)灌胃,正常组及AD组灌胃等剂量的生理盐水,均1次/d,灌胃时间连续60 d。采用Morris水迷宫实验观察认知功能; 苏木精-伊红(Hematoxy lin-Eosin,HE)染色观察海马组织病理学表现; 末端脱氧核苷酸转移酶介导的dUTP缺口末端标记测定法[Terminal dexynucleotidyl transferase(TdT)-mediated dUTP nick end labeling,TUNEL]法检测神经细胞凋亡率; 免疫印迹及实时定量聚合酶链反应(Quantitatie real time polymerase chain reaction,QRT-PCR)技术分别检测细胞色素C(Cytochrome c,Cyt-c),Caspase-3及Caspase-9蛋白及信使核糖核酸(Messenger RNA,mRNA)相对表达水平。结果 与正常组比较,AD组大鼠灌胃后第1～5 d的逃避潜伏期均延长(P<0.05); 与AD组比较, 干预A组、干预B组、干预C组逃避潜伏期均缩短(P<0.05),药物对照组逃避潜伏期与干预C组比较无明显差异(P>0.05)。与正常组比较,AD组大鼠游泳距离增加(P<0.05); 与AD组比较,干预A组、干预B组及干预C组大鼠游泳距离均减少(P<0.05),干预C组与药物对照组相似(P>0.05)。正常组海马结构完成,神经元排列紧密,细胞核清晰且无空泡; AD组大鼠海马组织结构紊乱,神经元数目减少,细胞核深染,细胞膜收缩及部分消失; APS干预组及药物对照组神经元排列较AD组整齐有序,肿胀程度减轻,细胞核较清晰。各组大鼠海马组织神经细胞凋亡率比较有明显差异(F=134.900,P<0.001); 与正常组比较,AD组神经细胞凋亡率升高(P<0.05); 与AD组比较,干预A组、干预B组及干预C组神经细胞凋亡率降低(P<0.05),药物对照组与干预C组神经细胞凋亡率相似(P>0.05)。与正常组比较,AD组海马组织Cyt-C,Caspase-3及Caspase-9蛋白及mRNA 相对表达水平上调(P<0.05); 与AD组比较,不同水平干预组海马组织Cyt-C,Caspase-3及Caspase-9蛋白及mRNA 相对表达水平下调(P<0.05),药物对照组与干预C组上述蛋白及mRNA相对表达水平相似(P>0.05)。结论 黄芪多糖能够改善AD大鼠认知功能,减轻海马组织病理损伤,抑制神经元凋亡且呈现水平依赖性,其机制可能与抑制Cyt-C及caspase-3/9信号通路有关。     

肉苁蓉多糖对阿尔茨海默病大鼠学习记忆及氧化应激影响的实验研究

目的 观察肉苁蓉多糖(Cistanche Deserticola,CDPS)对阿尔茨海默病(Alzhemer's disease,AD)模型大鼠学习记忆及氧化应激的影响,并探讨其可能治疗机制.方法 采用Aβ1～40侧脑室注射复制AD大鼠模型,并随机分为正常组、假手术组、模型组、肉苁蓉多糖低中高剂量组(50,100,200mg/kg-1d-1),每日予以相应药物灌胃治疗后检测大鼠学习记忆能力及脑组织中自由基代谢指标(SOD、MDA),并检测NO和ROS的变化.结果 肉苁蓉各剂量组均能显著降低大鼠实际逃避潜伏期(P＜0.01),明显提高SOD活性,降低MDA含量(P＜0.01);各剂量组均显著降低NO和ROS含量(P＜0.01).结论 肉苁蓉多糖治疗AD的机制可能与提高抗氧化能力、加速自由基清除实现的.     

姜黄素对阿尔茨海默病的治疗作用

姜黄是一种古印第安植物,最早作为调味品一咖喱粉和草药使用.现代医学研究发现,其粉末及提取物姜黄素能治疗各种疾病包括囊性纤维化、压疮、消化道溃疡、大肠癌、乳腺癌、动脉粥样硬化、肝病和关节炎[1].近年来研究发现,姜黄素对各种类型的痴呆和创伤性脑损伤有治疗作用,尤其在预防和治疗阿尔茨海默病(AD)方面具有重要作用.大量的证据表明,生物、金属毒素和异常炎症反应引起的氧化应激、自由基、β淀粉样蛋白、脑功能失调在AD的发病机制中起关键作用.姜黄素具有的抗氧化、抗炎和亲脂活性,能改善AD病人的认知功能,如缩小β淀粉样蛋白斑快、减缓神经元分解、鳌和金属、抗炎、抗氧化、减少小胶质细胞形成、改善AD病人整体记忆等[2].本文对姜黄素治疗AD的活性机制做一综述.     

脑缺血对阿尔茨海默病模型大鼠认知功能的影响及其机制探讨

目的 探讨脑缺血对阿尔茨海默病(AD)病程进展的影响及其机制.方法 采用大鼠海马注射凝聚态β-淀粉样蛋白(Aβ)1-40建立AD模型,再于海马内注射ET-1建立脑缺血条件,观察脑缺血后AD样大鼠认知功能以及海马内Aβ沉积、神经元丢失和异常磷酸化tau表达的变化;采用免疫组化、原位杂交和RT-PCR法检测海马内星形胶质细胞数量和IL-1、TNF-α表达的变化.结果 脑缺血后AD样大鼠的认知功能明显下降,海马内Aβ沉积增加,神经元丢失增加,异常磷酸化tau表达增加.星形胶质细胞的数量以及IL-1和TNF-α的表达显著增加(均P＜0.01).结论 脑缺血加重了AD样大鼠的认知功能障碍和海马病理损伤,显著增加的星形胶质细胞及IL-1和TNF-α的表达参与了这一过程.防治脑缺血和抗炎治疗可能成为减缓AD进展的新途径.     

黄芪改善缺血性脑损害的作用机制

黄芪是一种传统的心血管及抗病毒药物,主要含有贰类、多量糖分、氨基酸及微量元素,其中一些成分明显的药理作用已为研究所证实,其改善缺血神经元代谢、血液流变学以及对机体的免疫保护三方面的作用,是作为神经内、外科药物应用的主要机制。     

铝诱导阿尔茨海默病模型大鼠的发病机制的实验研究

目的探讨铝诱导的阿尔茨海默病(Alzheimer’s disease,AD)模型大鼠的发病机制。方法选择健康3月龄SD大鼠48只,随机分为对照组、模型组(分为低、中、高剂量铝饲料组),每组各12只。模型组在常规饲料中添加不同剂量A1C13.6H2O喂饲大鼠,持续染毒3个月,制做AD动物模型。实验结束后,麻醉大鼠、打开胸腔、右心室采血、分离血清保存、快速取大脑,分离海马并取一部分用以测定海马中AchE、ChAT的活性以及Ach含量,其余海马和其它脑组织称重并做脑匀浆,检测脑组织及血清SOD活性和MDA水平。结果中、高剂量铝饲料组大鼠海马中AchE的活性明显高于对照组(P<0.01),ChAT活性明显低于对照组(P<0.01),Ach含量亦显著减少(P<0.01);与对照组比较,中、高剂量铝饲料组大鼠脑组织及血清中SOD活性均明显降低(P<0.01),MDA含量显著增高(P<0.01)。结论铝的过多摄入使大鼠处于胆碱能系统失衡和氧化应激(oxidative stress,OS)状态,二者协同作用可能是AD发病的重要因素。     

二甲双胍对阿尔茨海默病大鼠的疗效及机制研究

目的 观察二甲双胍对阿尔茨海默病(Alzheimer's disease,AD)大鼠学习记忆能力的影响,并进一步探讨其可能机制.方法 将50只雄性SD大鼠随机分为正常组、假手术组、模型组和治疗组.模型组和治疗组大鼠双侧海马各注射5μl Aβ25-35(2 g/L)建立AD模型,假手术组注射等量生理盐水.次日,对治疗组大...     

阿尔茨海默病的胆碱能损害机制

阿尔茨海默病 (Alzheimer’s disease,AD)是一种以认知记忆障碍为特征的进行性神经系统变性疾病。随着人口老龄化程度增加 ,AD对人类健康的威胁将日趋严重 ,在发达国家 ,AD已被列为第四位死亡原因。 AD的发病机制非常复杂 ,存在着多种假说 ,但无法用一种假说完全解释 AD。目前多数学者认为脑内胆碱能系统的损害是造成 AD的重要原因 ,从而提出了“胆碱能假说”。本文就胆碱能神经损害的研究和治疗作一综述。1　 AD中胆碱能损害的特点中枢胆碱能递质在学习与记忆行为中有重要的调节作用 ,保持其功能正常 ,是维持哺乳动物学习记忆正常进…     

重视对阿尔茨海默病的分子机制与药物靶点的研究

阿尔茨海默病(Alzheimer’s disease，AD)是老年人常见的神经系统变性疾病，其临床特征为隐袭起病、持续进行性的智能衰退而无缓解。随着人类寺命的延长，人口老龄化问题的突出，对AD的防治已显得越来越重要。近年来，尽管在探索AD的发病机制和临床诊治方面取得了很大的进展，但迄今     

Alzheimer病的病理与临床诊断

对生前经过痴呆调查与临床诊断的９例老人院住院老人死亡后进行尸解神经病理学观察。结果发现９例尸检脑均有不同程度的萎缩与锥全细胞减少，脂褐素沉积，胶质细胞增生，淀粉样小体存在。其中３例尚在皮层与海在量老年斑（ＳＰｓ）与神经原纤维缠结（ＮＴＦｓ），病理确诊为Ａｌａｈｅｉｍｅｒ病（ＡＤ）；其余６例明确为非Ａｌｚｈｅｉｍｅｒ病老年脑（ＮＡＤ）。该病理结果与临床诊断全部痊愈，提示ＮＩＮＣＤＳ－ＡＤＲＤＡ之ＡＤ     

多奈哌齐治疗老年性痴呆的临床研究

目的:探讨乙酰胆碱和促炎症细胞因子在AD发病机制中的相互关系。方法:采用对照研究,对36名阿尔茨海默病(Alzheimer’sdisease,AD)患者用MMSE量表测定其治疗前后认知功能;采用Elisa方法测定乙酰胆碱酯酶抑制剂治疗前后脑脊液中白介素-1、肿瘤坏死因子、白介素-6等细胞因子的变化。结果:多奈哌齐组治疗24周后认知功能与治疗前比较明显提高,认知功能改善比脑复康组明显,同时CSF中IL-1、TNF-α、IL-6和sIL-6R的水平与治疗前相比,均明显降低且有显著意义(P<0.01)。结论:胆碱酯酶抑制剂多奈哌齐治疗AD,改善认知功能的同时,可使脑内促炎症细胞因子有所降低。提示胆碱能功能与促炎症细胞因子在AD发病中相互影响,具有密切联系。     

Alzheimer病的兴奋毒损伤机制

Alzheimer disease(AD）的多种致病因素造成GluR的改变,异常的GluR介导了Aβ及小胶质细胞的神经毒损害,促进tau蛋白的生成,引起G蛋白传导通路的改变,参与了自由基损害的细胞凋亡过程,从而加速了AD的发病。     

Parkinson病与Alzheimer病载脂蛋白E基因型分布的研究

目的探讨载脂蛋RE（apoE）基因多态性与Parkinson病及Alzheimer病的关系。方法应用聚合酶链反应-限制性片段氏度多态性（PCR－RFLP）技术检测72名帕金森氏病（PD）、68名Alzheimer病（AD）患者和66名正常老年人的apoE基因型分布。结果PD组apoE2、apoE3、apoE4及AD组apoE4等位基因频率与对照组比较无统计学意义（P＞0.05）;AD组apoE2等位基因频率明显低于对照组（P＜0．01）。结论apoE基因型分布与PD发病无关;与AD发病相关,即apoE2基因可能具有防止AD发病的作用;不支持apoE4是中国人散发性AD发病病危因素的结论。     

小檗碱对阿尔茨海默病大鼠模型小胶质细胞活化的影响

目的 研究小檗碱对阿尔茨海默病(AD)大鼠模型小胶质细胞活化的影响. 方法 18只SD大鼠按随机数字表法分为正常组、模型组和小檗碱组,每组各6只.后两组通过大鼠双侧海马立体定向注射凝聚态AB40(5 μg/L)建立AD大鼠模型,小檗碱组造模后灌胃给予小檗碱[50mg/(kg·d)]14 d.采用免疫组织化学法、实时荧光定量PCR法和Western blot法研究小檗碱对小胶质细胞活化标志物CD11b和炎症负调节因子过氧化物酶体增生物激活受体γ(PPARγ)表达的影响.结果模型组和小檗碱组大鼠海马CD11b阳性细胞数(74.0±13.4、121.5±19.9)、CD11b mRNA的相对拷贝数(4.08±2.43、5.52±1.83)较正常组(23.2±6.2、2.54±0.98)明显增加,PPARTγ阳性细胞数(42.5±5.6、31.7±8.7)、PPAR7mRNA的相对拷贝数(16.3±13.5、10.8±7.5)、PPARγ蛋白相对表达量(0.18±0.08、0.09±0.05)较正常组(93.2±11.3、40.6±17.1、0.31±0.111明显减少,比较差异有统计学意义;小檗碱组大鼠较模型组进一步增加海马CD11b阳性细胞数、CD11b mRNA的相对拷贝数和减少PPART阳性细胞数、PPARγ mRNA的相对拷贝数、PPARy蛋白相对表达量. 结论 小檗碱通过抑制PPARy的表达促进AD大鼠模型小胶质细胞的活化.     

Volumetric MRI and cognitive measures in Alzheimer disease

Background Both cognitive tests and MRI-based measures have been suggested as outcomes in trials assessing disease-modifying therapies in Alzheimer's disease (AD). Objective To compare changes in longitudinal MRI measures with changes in performance on cognitive tests routinely used in AD clinical trials. Method Fifty-two subjects from the placebo-arm of a clinical trial in mild-to-moderate AD had volumetric T₁-weighted scans and cognitive tests including the Mini-Mental State Examination (MMSE), AD Assessment Scale-Cognitive Subscale, Disability Assessment for Dementia, AD Cooperative Study-Clinical Global Impression of Change and Clinical Dementia Rating at baseline and one-year later. Rates of brain atrophy and ventricular enlargement were measured using the boundary shift integral. Hippocampal (Hc) atrophy was calculated from manual volume measurements. The relationships between MRI and cognitive measures were investigated. Results Rates of brain atrophy and/or ventricular enlargement were correlated with declining performance on cognitive scales. The strongest association was between brain atrophy rate and MMSE decline (r = 0.59, p < 0.0001). Hc atrophy rate was not significantly correlated with any of the cognitive scales. Conclusion The lack of correlation between Hc atrophy and cognitive scales may reflect a combination of: the extensive functional damage to the Hc by the time AD is clinically established, the greater influence of ongoing cortical degeneration, and errors in Hc outlining. The strong correlations between brain atrophy and ventricular enlargement, and cognitive scales probably reflect the correspondence between these measures of overall cerebral loss and global cognitive measures in the moderate stages of AD. Disclosure Sponsored by Elan Pharmaceuticals, Inc., and Wyeth Research. Drs. Fox and Rossor have received honoraria from Elan Pharmaceuticals, Inc., and Wyeth Research. Dr Black is an employee of, holds equity in excess of $10.000 in, and has received honoraria in excess of $10.000 from Wyeth Research. Dr Grundman is an employee of Elan Pharmaceuticals, Inc., and holds equity in its parent company, Elan Corporation plc.     

Alzheimer''s disease and senile dementia of Alzheimer type

Clinical and neuropsychological findings, EEG, and several blood and CSF parameters were investigated in 36 patients with Alzheimer's disease (AD) and 35 patients with senile dementia of Alzheimer type (SDAT). There were more women among senile patients and more familial cases among presenile patients. The average duration of the symptoms was longer in presenile patients (6.1 years) than in senile patients (3.9 years). This could be due to the lower resistance to the disease process in the senile group.
Extrapyramidal signs, especially rigidity, were found in over 60 % of all patients and in practically all patients with advanced dementia. Tremor was found in three patients only. Four presenile (11 %) and two senile (6 %) patients had epileptic seizures. All patients had abnormal EEG recordings, mainly in form of diffuse slowing. A positive correlation was found between the EEG abnormality and the severity of dementia in AD but not in SDAT. However, the difference between the correlation coefficients in AD and SDAT was insignificant. Between EEG and the duration of the disease there was no correlation. EEG was not more abnormal in very severe dementia than in severe dementia. Other findings were similar in AD and SDAT.
It is concluded that it is artificial to separate AD and SDAT at the age of 65 and that they clinically compose a single entity. This entity could well be called Alzheimer's disease.     

Abnormalities of mitochondrial enzymes in Alzheimer disease

Summary. Abundant evidence, including critical information gathered by Prof. Siegfried Hoyer and his colleagues, indicates that abnormalities of cerebral metabolism are common in neurodegenerative diseases, including Alzheimer's Disease (AD). Alterations in mitochondrial enzymes likely underlie these deficits. Replicable reductions in AD brain occur in the pyruvate dehydrogenase complex (the link of glycolysis to the Kreb's cycle), the α-ketoglutarate dehydrogenase complex (KGDHC; the link of Kreb's cycle to glutamate metabolism) and cytochrome oxidase (the link of the Kreb's cycle to oxygen utilization). Available evidence suggests that deficiencies in KGDHC may be genetic in some cases, whereas evidence that the other two enzyme systems have a genetic component is lacking. Additional results indicate that the reductions can also be secondary to other causes including oxidative stress. A variety of data suggest that the mitochondrial insufficiencies contribute significantly to the pathophysiology of AD. Received April 29, 1998; accepted May 20, 1998     

They have shaped Alzheimer disease: the protagonists, well known and less well known

This paper discusses the history of dementia and Alzheimer's disease (AD) with emphasis on the individuals who have shaped its development. In addition to the best known protagonists recognized as founders of the field, it will mention other figures who have provided important contributions but are sometimes overlooked. Many of these have also become famous for work unrelated to AD.