银思维对拟SAD大鼠脑内tau磷酸化及其O-GlcNAc修饰的调节作用及相关研究
|
摘要
目的：基于胰岛素信号转导与散发性老年性痴呆(SAD)的关系及SAD发病的脑能量代谢障碍学说与tau蛋白异常修饰学说,以大鼠侧脑室注射链脲佐菌素(ICV-STZ)建立SAD动物模型,研究具有升发阳气,祛逐阴邪,健脾开郁化痰、平衡机体阴阳功效的中药复方银思维提取物对SAD模型大鼠的行为学、海马神经元超微结构、脑能量代谢及胆碱能系统相关酶的活性、脑组织tau蛋白磷酸化与O-G1cNAc糖基化修饰的影响及调节作用,探讨复方银思维防治SAD的可能作用机制。
方法：将SPF级健康雄性SD大鼠随机分为假手术组、模型组、多奈哌齐对照组、银思维小、中、大剂量组。除假手术组外,其余动物双侧侧脑室重复注射STZ造模,第二次造模后21天开始治疗。治疗组分别以盐酸多奈哌齐、银思维大、中、小不同剂量浓度灌胃,模型组及假手术组给予等体积的双蒸水,各组均每日1次,共灌胃2个月。治疗结束后,以MOrris水迷宫试验法测试大鼠的空间学习记忆能力,以透射电镜观察大鼠海马CA1区微管等超微结构的变化,以生化方法测定大鼠大脑皮层能量代谢与线粒体功能相关酶以及胆碱能系统酶的活性,以免疫组化及蛋白印迹方法检测大鼠脑组织tau蛋白O-G1cNAc糖基化修饰水平及重要位点Thr231、Ser422的磷酸化水平,同时检测O-G1cNAc糖基化修饰过程中OGT、O—G1cNAcase酶表达的变化。
结果：
1.ICV-STZ拟SAD模型大鼠与假手术组相比,在定向航行试验中的平均逃避潜伏期及总游泳距离显著延长(P<0.01),空间探索试验中在目标象限的游泳时间明显缩短(P<0.01)。复方银思维能明显缩短SAD模型大鼠在定向航行试验中的平均逃避潜伏期及总游泳距离,组间比较差异有统计学意义(P<0.05,P<0.01),且能延长SAD大鼠空间探索试验中在目标象限的游泳时间(P<0.05,P<0.01)。银思维小、中、大剂量组与多奈哌齐组组间比较无显著性差异(P>0.05)
2.SAD模型组大鼠大脑皮层SDH、COX、Na+-K+-ATPase活性明显低于假手术组(P<0.01),而复方银思维能显著提高SAD大鼠皮层SDH、COX、Na+-K+-ATPase的活性(P<0.05,P<0.01),多奈哌齐对照组与SAD模型组相比则无显著性差异(P>0.05)
3.SAD模型组大鼠大脑皮层ChAT活性明显低于假手术组(P<0.01),而AchE活性高于假手术组(P<0.01),复方银思维能够提高大鼠大脑皮层ChAT活性,同时使得AchE活性下降,组间差异有统计学意义(P<0.05,P<0.01),多奈哌齐组与银思维小、中、大剂量组组间比较无显著性差异(P>0.05)
4.SAD模型大鼠海马组织以sWGA富集的O-G1cNAc糖基化蛋白质明显低于假手术组(P<0.01),且用RL2、CTD110.6抗体检测的O-G1cNAc糖基化tau蛋白表达明显低于假手术组(P<0.01)；而复方银思维能明显提高SAD大鼠海马组织以sWGA富集的O-G1cNAc糖基化蛋白质以及用RL2、CTD110.6检测的O-G1cNAc糖基化tau蛋白表达,组间差异有统计学意义(P<0.05,P<0.01)。多奈哌齐对照组与SAD模型组相比则无显著性差异(P>0.05)。
5.SAD模型大鼠海马组织OGT的表达明显低于假手术组(P<0.01)O-G1cNAcase表达明显高于假手术组(P<0.01),而复方银思维能显著提高SAD大鼠海马OGT的表达,降低O-G1cNAcase的表达,组间差异有统计学意义(P<0.05,P<0.01)。多奈哌齐对照组与SAD模型组相比无显著性差异(P>0.05)
6.SAD模型大鼠海马组织tau蛋白在重要位点Thr231和Ser422的磷酸化P-Thr231、P-Ser422表达高于假手术组(P<0.01),而复方银思维能减少SAD模型大鼠海马组织P-Thr231、P-Ser422的表达(P<0.05,P<0.01)。多奈哌齐对照组与SAD模型组相比则无显著性差异(P>0.05)
结论：
1. ICV-STZ模型大鼠存在脑皮层能量代谢与线粒体功能障碍,存在胆碱能系统紊乱,有明显的学习记忆障碍,有脑组织tau蛋白重要位点的异常磷酸化,且模型重复性好,稳定可靠,可以作为SAD模型。
2.复方银思维能明显改善SAD大鼠的学习记忆能力,其作用机制可能是：能够保护微管结构和功能,改善皮层神经元线粒体功能及能量代谢,改善皮层胆碱能系统功能,调节海马组织tau蛋白O-G1cNAc糖基化修饰与tau磷酸化之间的平衡,抑制tau蛋白重要位点的过度磷酸化及其tau毒性,防止SAD的病理进展。
Objective:Based on the relation of insulin-signaling transmission and sporadic Alzheimer disease (SAD) and also on the theory of energy metabolism disorder in brain and the theory of tau normal modification, this paper aims at studying the effects of YSW-compound on the ethology of model rats with SAD, ultrastructure of hippocampal neurons, energy metabolism in brain, the activity of enzyme related cholinergic system, phosphorylation of tau protein in brain t issue and glycosylated modification of 0-GlcNAc, and also discussing the possible mechanism of protection and treatment of YSW-compound on SAD. YSW-compound is characterized by ascending yang qi, dispelling pathogenic yin, expelling stagnation, removing phlegm and balancing yin and yang. The dementia model (ICV-SAD) was established by intracerebroventricular injection of streptozotocin (ICV-STZ).
Methods:SPF healthy male Sprague-Dawley (SD) rats were divided into six groups randomly:sham-operation group, model group, donepezil control group, YSW low dose, medium dose and high dose groups. The dementia model was established by bilateral intracerebroventricular injection of streptozotocin and their treatment was started on 21st after the second modeling except sham operation group and model group. The treatment groups were given the corresponding drugs respectively through gavage. Meanwhile, model group and sham operation group were given the same volume of distilled water through gavage once per day for two months. After the treatment, the Morris water maze was adopted to test spatial learning and memory ability of the rats. The ultrastructural changes of microtubes in hippocampal CA1 of rats were observed by electron microscope. The energy metabolism of cerebral cortex and the activity of enzyme related mitochondrial function and cholinergic system enzyme were tested by biochemical technique. The immunohistochemistry and western-blot methods were used to test the glycosylated modification levels of tau protein 0-G1 cNAc in brain tissue and the phosphorylated levels in the Thr231 and Ser422 sites, along with the expression changes of OGT and 0-G1 cNAcase enzyme in the process of 0-GlcNAc glycosylated modification.
Results:
1. Compared with sham operation group, the mean escape latency and total swimming distance of rats with SAD (by ICV-STZ) during place navigation test was longer (P<0.01), but the swimming time of rats with SAD in target quadrant was obviously shorter during space probe test (P<0.01). YSW-compound could significantly shorten the mean escape latency and total swimming distance of rats with SAD during place navigation test, with statistical significance (P<0.05, P<0.01) and could extend the swimming time of rats with SAD in target quadrant during space probe test (P<0.05, P<0.01). Donepezil group, compared with YSW low dose, medium dose and high dose groups respectively, had no significant difference (P>0.05).
2. The activity of SDH, COX and Na+-K+-ATPase in cerebral cortex of rats with SAD in model group was lower than sham operation group (P<0.01), while YSW-compound could increase the activity of SDH, COX and Na+-K+-ATPase in cerebral cortex of rats(P<0.05, P<0.01). Donepezil group had no obvious difference in comparison with model group (P>0.05).
3. Compared with sham operation group, the activity of ChAT in cerebral cortex of rats with SAD in model group was lower (P<0.01), but the activity of AchE was higher (P<0.01). YSW-compound could increase the activity of ChAT in cerebral cortex of rats and reduce the activity of AchE with statistical significance (P<0.05, P<0.01). Donepezil group, compared with YSW low dose,medium dose and high dose groups respectively, had no significant difference (P>0.05).
4. Compared with sham operation group, the glycoproteomics of O-GlcNAc in hippocampal tissue with sWGA enrichment of rats with SAD was lower (P<0.01) and the expression of glycosylated tau protein tested by RL2 and CTD110.6 was also lower (P<0.01). However, YSW-compound could obviously improve the glycoproteomics of O-GlcNAc in hippocampal tissue with sWGA enrichment of rats with SAD and the expression of glycosylated tau protein tested by RL2 and CTD110.6, with statistical significance (P<0.05, P<0.01). Donepezil group had no significant difference from the model group (rats with SAD) (P>0.05).
5. Compared with sham operation group, the expression of OGT in hippocampal tissue of rats with SAD was obviously lower (P<0.01) but the expression of O-GlcNAcase was remarkably higher (P<0.01). However, YSW-compound could significantly improve the expression of OGT in hippocampal tissue of rats with SAD and reduce the expression of O-GlcNAcase, with statistical meaning (P<0.05, P<0.01). Donepezil group had no significant difference from the model group (rats with SAD) (P>0.05).
6. Compared with sham operation group, the expression of phosphorylated P-Thr231 and P-Ser422 of tau protein in hippocampal tissue in the Thr231 and Ser422 sites in model group was significantly higher (P<0.01), while YSW-compound could remarkably reduce the expression of P-Thr231 and P-Ser422 of hippocampal tissue of rats with SAD (P<0.05, P<0.01). Donepezil group had no significant difference from the model group (rats with SAD) (P>0.05).
Conclusion:
1. The ICV-STZ model rats with SAD is characterized by disorders with the energy metabolism of cerebral cortex, mitochondrial function and cholinergic system, along with the impairment of learning and memory and the abnormal phosphorylat ion of tau protein in the key sites of brain tissue. Moreover, the model has good repeatability, stability and reliability, and also is very appropriate to be used to do basic research and drug screening on rats with SAD.
2. YSW-compound could significantly improve the learning and memory ability of rats with SAD and the function of neuron mitochondria in cerebral cortex of rats with SAD, and also adjust the balance between the glycosylated mod if icat ion of tau protein 0-G1 cNAc and the phosphorylat ion in hippocampal tissue. YSW-compound could inhibit the hyperphosphorylation of tau protein in the key sites and the toxicity of tau, and protect the structure and function of microtubes as well as prevent axons from injury
方法：将SPF级健康雄性SD大鼠随机分为假手术组、模型组、多奈哌齐对照组、银思维小、中、大剂量组。除假手术组外,其余动物双侧侧脑室重复注射STZ造模,第二次造模后21天开始治疗。治疗组分别以盐酸多奈哌齐、银思维大、中、小不同剂量浓度灌胃,模型组及假手术组给予等体积的双蒸水,各组均每日1次,共灌胃2个月。治疗结束后,以MOrris水迷宫试验法测试大鼠的空间学习记忆能力,以透射电镜观察大鼠海马CA1区微管等超微结构的变化,以生化方法测定大鼠大脑皮层能量代谢与线粒体功能相关酶以及胆碱能系统酶的活性,以免疫组化及蛋白印迹方法检测大鼠脑组织tau蛋白O-G1cNAc糖基化修饰水平及重要位点Thr231、Ser422的磷酸化水平,同时检测O-G1cNAc糖基化修饰过程中OGT、O—G1cNAcase酶表达的变化。
结果：
1.ICV-STZ拟SAD模型大鼠与假手术组相比,在定向航行试验中的平均逃避潜伏期及总游泳距离显著延长(P<0.01),空间探索试验中在目标象限的游泳时间明显缩短(P<0.01)。复方银思维能明显缩短SAD模型大鼠在定向航行试验中的平均逃避潜伏期及总游泳距离,组间比较差异有统计学意义(P<0.05,P<0.01),且能延长SAD大鼠空间探索试验中在目标象限的游泳时间(P<0.05,P<0.01)。银思维小、中、大剂量组与多奈哌齐组组间比较无显著性差异(P>0.05)
2.SAD模型组大鼠大脑皮层SDH、COX、Na+-K+-ATPase活性明显低于假手术组(P<0.01),而复方银思维能显著提高SAD大鼠皮层SDH、COX、Na+-K+-ATPase的活性(P<0.05,P<0.01),多奈哌齐对照组与SAD模型组相比则无显著性差异(P>0.05)
3.SAD模型组大鼠大脑皮层ChAT活性明显低于假手术组(P<0.01),而AchE活性高于假手术组(P<0.01),复方银思维能够提高大鼠大脑皮层ChAT活性,同时使得AchE活性下降,组间差异有统计学意义(P<0.05,P<0.01),多奈哌齐组与银思维小、中、大剂量组组间比较无显著性差异(P>0.05)
4.SAD模型大鼠海马组织以sWGA富集的O-G1cNAc糖基化蛋白质明显低于假手术组(P<0.01),且用RL2、CTD110.6抗体检测的O-G1cNAc糖基化tau蛋白表达明显低于假手术组(P<0.01)；而复方银思维能明显提高SAD大鼠海马组织以sWGA富集的O-G1cNAc糖基化蛋白质以及用RL2、CTD110.6检测的O-G1cNAc糖基化tau蛋白表达,组间差异有统计学意义(P<0.05,P<0.01)。多奈哌齐对照组与SAD模型组相比则无显著性差异(P>0.05)。
5.SAD模型大鼠海马组织OGT的表达明显低于假手术组(P<0.01)O-G1cNAcase表达明显高于假手术组(P<0.01),而复方银思维能显著提高SAD大鼠海马OGT的表达,降低O-G1cNAcase的表达,组间差异有统计学意义(P<0.05,P<0.01)。多奈哌齐对照组与SAD模型组相比无显著性差异(P>0.05)
6.SAD模型大鼠海马组织tau蛋白在重要位点Thr231和Ser422的磷酸化P-Thr231、P-Ser422表达高于假手术组(P<0.01),而复方银思维能减少SAD模型大鼠海马组织P-Thr231、P-Ser422的表达(P<0.05,P<0.01)。多奈哌齐对照组与SAD模型组相比则无显著性差异(P>0.05)
结论：
1. ICV-STZ模型大鼠存在脑皮层能量代谢与线粒体功能障碍,存在胆碱能系统紊乱,有明显的学习记忆障碍,有脑组织tau蛋白重要位点的异常磷酸化,且模型重复性好,稳定可靠,可以作为SAD模型。
2.复方银思维能明显改善SAD大鼠的学习记忆能力,其作用机制可能是：能够保护微管结构和功能,改善皮层神经元线粒体功能及能量代谢,改善皮层胆碱能系统功能,调节海马组织tau蛋白O-G1cNAc糖基化修饰与tau磷酸化之间的平衡,抑制tau蛋白重要位点的过度磷酸化及其tau毒性,防止SAD的病理进展。
Objective:Based on the relation of insulin-signaling transmission and sporadic Alzheimer disease (SAD) and also on the theory of energy metabolism disorder in brain and the theory of tau normal modification, this paper aims at studying the effects of YSW-compound on the ethology of model rats with SAD, ultrastructure of hippocampal neurons, energy metabolism in brain, the activity of enzyme related cholinergic system, phosphorylation of tau protein in brain t issue and glycosylated modification of 0-GlcNAc, and also discussing the possible mechanism of protection and treatment of YSW-compound on SAD. YSW-compound is characterized by ascending yang qi, dispelling pathogenic yin, expelling stagnation, removing phlegm and balancing yin and yang. The dementia model (ICV-SAD) was established by intracerebroventricular injection of streptozotocin (ICV-STZ).
Methods:SPF healthy male Sprague-Dawley (SD) rats were divided into six groups randomly:sham-operation group, model group, donepezil control group, YSW low dose, medium dose and high dose groups. The dementia model was established by bilateral intracerebroventricular injection of streptozotocin and their treatment was started on 21st after the second modeling except sham operation group and model group. The treatment groups were given the corresponding drugs respectively through gavage. Meanwhile, model group and sham operation group were given the same volume of distilled water through gavage once per day for two months. After the treatment, the Morris water maze was adopted to test spatial learning and memory ability of the rats. The ultrastructural changes of microtubes in hippocampal CA1 of rats were observed by electron microscope. The energy metabolism of cerebral cortex and the activity of enzyme related mitochondrial function and cholinergic system enzyme were tested by biochemical technique. The immunohistochemistry and western-blot methods were used to test the glycosylated modification levels of tau protein 0-G1 cNAc in brain tissue and the phosphorylated levels in the Thr231 and Ser422 sites, along with the expression changes of OGT and 0-G1 cNAcase enzyme in the process of 0-GlcNAc glycosylated modification.
Results:
1. Compared with sham operation group, the mean escape latency and total swimming distance of rats with SAD (by ICV-STZ) during place navigation test was longer (P<0.01), but the swimming time of rats with SAD in target quadrant was obviously shorter during space probe test (P<0.01). YSW-compound could significantly shorten the mean escape latency and total swimming distance of rats with SAD during place navigation test, with statistical significance (P<0.05, P<0.01) and could extend the swimming time of rats with SAD in target quadrant during space probe test (P<0.05, P<0.01). Donepezil group, compared with YSW low dose, medium dose and high dose groups respectively, had no significant difference (P>0.05).
2. The activity of SDH, COX and Na+-K+-ATPase in cerebral cortex of rats with SAD in model group was lower than sham operation group (P<0.01), while YSW-compound could increase the activity of SDH, COX and Na+-K+-ATPase in cerebral cortex of rats(P<0.05, P<0.01). Donepezil group had no obvious difference in comparison with model group (P>0.05).
3. Compared with sham operation group, the activity of ChAT in cerebral cortex of rats with SAD in model group was lower (P<0.01), but the activity of AchE was higher (P<0.01). YSW-compound could increase the activity of ChAT in cerebral cortex of rats and reduce the activity of AchE with statistical significance (P<0.05, P<0.01). Donepezil group, compared with YSW low dose,medium dose and high dose groups respectively, had no significant difference (P>0.05).
4. Compared with sham operation group, the glycoproteomics of O-GlcNAc in hippocampal tissue with sWGA enrichment of rats with SAD was lower (P<0.01) and the expression of glycosylated tau protein tested by RL2 and CTD110.6 was also lower (P<0.01). However, YSW-compound could obviously improve the glycoproteomics of O-GlcNAc in hippocampal tissue with sWGA enrichment of rats with SAD and the expression of glycosylated tau protein tested by RL2 and CTD110.6, with statistical significance (P<0.05, P<0.01). Donepezil group had no significant difference from the model group (rats with SAD) (P>0.05).
5. Compared with sham operation group, the expression of OGT in hippocampal tissue of rats with SAD was obviously lower (P<0.01) but the expression of O-GlcNAcase was remarkably higher (P<0.01). However, YSW-compound could significantly improve the expression of OGT in hippocampal tissue of rats with SAD and reduce the expression of O-GlcNAcase, with statistical meaning (P<0.05, P<0.01). Donepezil group had no significant difference from the model group (rats with SAD) (P>0.05).
6. Compared with sham operation group, the expression of phosphorylated P-Thr231 and P-Ser422 of tau protein in hippocampal tissue in the Thr231 and Ser422 sites in model group was significantly higher (P<0.01), while YSW-compound could remarkably reduce the expression of P-Thr231 and P-Ser422 of hippocampal tissue of rats with SAD (P<0.05, P<0.01). Donepezil group had no significant difference from the model group (rats with SAD) (P>0.05).
Conclusion:
1. The ICV-STZ model rats with SAD is characterized by disorders with the energy metabolism of cerebral cortex, mitochondrial function and cholinergic system, along with the impairment of learning and memory and the abnormal phosphorylat ion of tau protein in the key sites of brain tissue. Moreover, the model has good repeatability, stability and reliability, and also is very appropriate to be used to do basic research and drug screening on rats with SAD.
2. YSW-compound could significantly improve the learning and memory ability of rats with SAD and the function of neuron mitochondria in cerebral cortex of rats with SAD, and also adjust the balance between the glycosylated mod if icat ion of tau protein 0-G1 cNAc and the phosphorylat ion in hippocampal tissue. YSW-compound could inhibit the hyperphosphorylation of tau protein in the key sites and the toxicity of tau, and protect the structure and function of microtubes as well as prevent axons from injury
引文
[1]陈可冀.跨世纪脑科学-老年性痴呆发病机理与诊治.北京：北京医科大学中国协和医科大学联合出版社,1998
[2]Alzheimer's-Association.2009 Alzhemier's disease facts and figures. Alzhemiers-Dement.2009; 5(3):234-70
[3]Zhang ZX, Zahner GE, Roman GC, et a.l. Dementia subtypes in China: prevalence in Beijing, Xian, Shangha, i and Chengdu. Arch Neuro.2005; 62:447-453.
[4]Ferri CP, Prince M, Brayne C, et a.l. Global prevalence of dementia: a Delphi consensus study. Lancet.2005; 366:2112-2117.
[5]Webber KM,Raina AK,Marlatt MW,et al.The cell cycle in Alzheimer disease:unique target for neuropharmacology. Mechanisms of Ageing and Development.2005; 126:1019-1025
[6]CsermelyP, Agoston V, PongorS. The effieiency of multitarget drugs:the network approach might help drug design[J]. Trends pharmacol Sci.2005; 26 (4) 178-182.
[7]中华全国中医学会老年医学会.老年呆病的诊断辨证分型及疗效评定标准(讨论稿)[J].中医杂志.1991,(2):56-57
[8]谢娟.基于数理统计的老年期痴呆方组方配伍规律研究.南京中医药大学博士学位论文.2009
[9]王晓林,巴哈尔·哈德尔.明清时期治疗老年性痴呆的用药规律.光明中医.2010,25(5)：749
[10]刘维宾,刘维政.历代运用益智方药规律的探讨.江西中医药.2005,36(8):62-63
[11]魏翠柏,田金洲,贾建平.老年痴呆中医病因病机理论的认识与思考[J].中华中医药杂志.2005,20(8)：496-497
[12]王永炎,严世芸.实用中医内科学(第二版)上海科技出版社,2009:455-456
[13]余锐,肖飞,李晓光,等.去痴灵脂溶性提取物血清抑制M146L细胞分泌β淀粉样蛋白[J].中国新药杂志.2006,15(13):1061
[14]张建民,胡愉,王红,等.中药复方CHP Ⅱ对PDAPP转基因小鼠脑组织病变的影响[J].解剖学报.2004,35(6)：622
[15]张婷,董克礼.益智健脑颗粒对阿尔茨海默病患者脑脊液β淀粉样蛋白含量的影响[J].中国老年学杂志.2007,27(6):1080
[16]田金洲,朱爱华,钟剑.金思维治疗社区轻度认知损害老年患者记忆减退症状的1年随访[J].中国中药杂志.2003,28(10)：987-991
[17]成龙.中药金思维对A β所致AD大鼠模型脑血管和神经元损伤的保护机制研究.北京中医药大学博士研究生学位论文.2003
[18]李小黎.金思维提取物对A β致类AD模型神经元突触的保护作用及其机制研究.北京中医药大学博士研究生学位论文.2004
[19]徐意.金思维提取物对AD模型鼠脑内β淀粉样肽及神经可塑性的影响.北京中医 药大学博士研究生学位论文.2005
[20]张雷明.金思维提取物对AD模型小鼠脑内β-淀粉样肽生成与降解的调节作用.北京中医药大学博士研究生学位论文.2009
[21]温世荣,王德生,张景艳,等.复智散对淀粉样β蛋白25-35神经细胞毒性效应的影响及其机制[J].中国临床康复.2005,9(13)：248
[22]俭剑非,任常山,尹元琴.EGb761对阿尔茨海默病大鼠脑内ChAT活性及神经元凋亡的影响[J].中国实用内科杂志.2007,27(10):792
[23]钟振国,屈泽强,王乃平,等.三七总皂苷对阿尔茨海默病大鼠脑胆碱能神经的保护作用[J].中国临床康复.2006,10(19)：174
[24]王晓英,陈霁,张均田.人参皂苷Rg1对β 2淀粉样肽(25-35)侧脑室注射所致小鼠学习记忆障碍的改善作用及其机制[J].药学学报.2001,36(1):1-4
[25]刘卫刚,肖向建,李敏,等.石杉碱甲对体外培养大鼠脊髓片前角运动神经元损伤的保护作用[J].中国新药与临床杂志.2005,24(12)：933-937
[26]章海燕,唐希灿.石杉碱甲：具有治疗神经退行性疾病的前景药物[J].上海医药.2003,24(3)：112 120.
[27]曾育琦,陈晓春,黄春等.人参皂苷Rgl通过调节GSK23 (βPPP2A活性减轻皮层神经元Tau蛋白过度磷酸化.解剖学报.2007,38(6)：665-667
[28]谢玉华,陈晓春,张静等.人参皂苷可能通过CDK5途径减轻A β 25-35诱导的胎鼠海马神经元tau蛋白过度磷酸化[J].药学学报.2007,42：828-832
[29]宋锦秋,陈晓春,张静,等.人参皂苷Rbl通过JNK_p38 MAPK途径减轻A β 25-35诱导的胎鼠皮层神经元tau蛋白过度磷酸化[J].药学学报.2008,43:29-34
[30]李国栋,袁保梅,鄢文海等.人参皂苷Rbl对内源性A β所致小鼠神经细胞tau蛋白过磷酸化的干预作用.山东医药.2009,49(3)：26-27
[31]钟雷,谭洁,欧阳石等.知母皂苷B对大鼠海马注射A β 25-35致tau蛋白磷酸化的影响[J].南方医科大学学报.2006,26(8)：1106-1109
[32]Peng JH,Zhang CE,Wei W, Hong XP, Pan XP, Wang JZ. Dehydroevodiamine attenuates tau hyperphosphorylation and spatial memory deficit induced by activation of glycogen synthase kinase-3 in rats[J]. Neuropharmacology 2007;52:1521-1527
[33]顾明,周慧芳,薛冰,等.雷公藤单体T10对A β1-42所致PC1 2细胞调亡的抑制作用[J].生理学报.2004,56(1)：73
[34]吴蕾,陈云波,王奇,等.人参皂苷对A β 25235蛋白诱导的老年性痴呆体外模型NG10821 5神经元细胞凋亡的抑制作用[J].广州中医药大学学报.2007,24(2)：126
[35]李龙宣,赵斌,许志恩,等.熟地黄抑制阿尔茨海默病样大鼠海马神经元凋亡的作 用[J].中华神经医学杂志.2006,5(1)：10
[36]谢宁,宋琳,姚丽芬,等.地黄饮子对阿尔茨海默病模型鼠脑神经元细胞凋亡及超微结构的影响[J].中国临床康复.2005,9(37)：93
[37]王小艳,董军,陆大祥,等.中药复方SM I对拟老年痴呆小鼠学习记忆能力及海马BDNF表达的影响[J].中国病理生理杂志.2005,21(3)：524
[38]张兰,李林,李斌等.中药参乌胶囊对老年大鼠学习记忆及海马组织学的影响[J]中国康复理论与实践.2002,8(9)：516
[39]黄理钧,龚俊华,梁烨,等.益智健脑颗粒对AD模型大鼠学习记忆能力及海马神经元BDNF表达的影响[J].中国行为医学科学.2006,15(9):780
[40]丁向东,冯月英,张健新,等.升黄益智方对氯化铝所致痴呆模型小鼠行为学及脑组织神经递质的影响[J].中国老年学杂志.2004,24(12):1183
[41]康湘萍,金国琴,赵伟康,等.调心方有效部位TX0201对A β 25-35所致类“AD”大鼠氧化损伤及能量代谢的影响[J].中药药理与临床.2005,21(2):23
[42]杨戈,林水淼,赵伟康,等.达纳康对类老年痴呆大鼠脑组织胶质细胞原纤维酸性蛋白和IL21 β、IL26及APPmRNA表达的影响[J].北京中医药大学学报.2006,29(12)：816
[43]张桂娟,马民,马义.脑康冲剂治疗阿尔茨海默病的临床与实验研究[J].中国老年学杂志.2006,26:619
[44]周志昆,曾红兵.黄芪三仙汤对Alzheimer模型大鼠脑海马区免疫炎性反应的影响[J].中药药理与临床.2006,22(2)：48
[45]Bubber P, Haroutumian V, Fish G, et al. Mitochondrial abnormalities in Alzheimer brain:mechanistic implications[J]. Ann Neurol.2005; 57 (5):695
[46]赵丽波,张林,邬英全,等.A β 25-35致PC12细胞膜线粒体损伤及人参皂苷对其影响[J].中国实验诊断学.2005,9(1)：67-69
[47]姚柏春,袁华,黄翔,等.喂饲绞股蓝皂苷对Aβ1-40注射海马后大鼠脑内COX活性和线粒体超微结构变化的影响[J].中国老年学杂志.2005,25(10):1193
[48]王杉,蒋宁,周文霞等.黄连解毒汤对快速老化模型小鼠海马蛋白表达的影响[J].中国中药杂志.2007,32(21)：2289-2294
[49]徐建民.益智汤抗老年期痴呆的实验研究[J].中国中医药科技,2007,14(4):279.
[50]蔡大勇,陈金星,张伟.丹栀逍遥散干预D2半乳糖拟老年性痴呆大脑能量物质代谢的机制研究[J].航天医学与医学工程.2005,18(2):32
[51]沈映君.中药药理学[M].北京：人民卫生出版社,2000
[52]张均田.人参皂苷Rgl的促智作用机制对神经可塑性和神经发生的影响[J].药学学报.2005,40(5)：385-388
[53]中国医学科学院药物研究所.中草药现代研究(第二卷).北京：北京医科大学中 国协和医科大学联合出版社.1996.440,442,450,444
[54]黄芪、构杞子对衰老大鼠SOD,LPO及其某些激素的影响[J].中药药理与临床.1999,18(6)：20
[55]杨敏.黄芪对慢性低02高C02大鼠学习记忆能力的影响[J].中国热带医学.2008,8(1)：28-29
[56]尹艳艳,公惠玲,李维祖,等.黄芪总苷对血管性痴呆小鼠学习记忆功能的影响[J].安徽医药,2009,13(9)：1018-1020.
[57]李献平等.四大怀药延缓衰老作用的研究[J].中西医结合杂志.1991,11(8)：486
[58]郝志奇,等.山药水煎剂对实验性小鼠的降血糖作用[J].中国药科大学学报.1991,22(3)158
[59]吕圭源,李万里.白术抗衰老作用研究[J].现代应用药学.1996,13(5):26-29
[60]李怀荆,郭忠兴.白术水煎剂对老年小鼠抗衰老作用的影响[J].佳木斯医学学报.1996,19(1)：9
[61]明亮,等.白芍总苷对小鼠学习记忆行为的影响.安徽医科大学学报.1993,28(1):19
[62]刘一流,李续娥.何首乌蛋白质和葸醌苷对D-半乳糖衰老小鼠学习记忆及代谢产物的影响[J].广州中医药大学学报.2009,26(2)：160-163.
[63]刘孟渊,刘惠纯.益智中草药的研究概况[J].中国中西医结合杂志.2002,15(1):59
[64]王月芳,万海同.论肾虚痰凝血瘀是老年性痴呆的重要发病机制[J].中国中医基础学杂志.2001,5(8)：9
[65]聂晶,罗勇,龚其海,等.淫羊藿苷对三氯化铝诱导痴呆大鼠模型脑内胆碱能系统的影响[J].上海中医药杂志.2008,42(4)：69-72
[66]楚晋,李林,叶翠飞,等.淫羊藿黄酮对APP转基因小鼠学习记忆及β-amyloid生成的影响[J].中国科学技术大学学报.2008,38(4)：439-448
[67]唐洪梅,李锐,周莉玲.石菖蒲对中枢神经系统作用研究进展[J].广州中医药大学学报.2000(2)：21
[68]黄兆胜.中药对老年性痴呆中枢神经递质改变调节[J].时珍国医国药.1999,10(9)：699
[69]陈勤,高晨曦,葛礼浩.远志皂苷对脑定位注射Aβ1-40拟AD大鼠脑内神经形态病理学变化的影响[J].激光生物学报.2006,15(3)：294-298
[7 0]陈勤,曹炎贵,张传惠.远志皂苷对β-淀粉样肽和鹅膏氨酸引起胆碱能系统功能降低的影响[J].药学学报.2002,37(12)：913-917
[71]Kim H M, Lee E H, Na H J, et al. Effect of polygalatenuifolia root extract on the tumor necrosis factor-a secretion from mouse astrocytes [J].J Ethnop-harmacol.1998; 61:201-208
[72]穆俊霞,李新毅.中药远志对阿尔茨海默病大鼠模型学习记忆和胆碱酯酶活性的影响[J].世界中西医结合杂志.2007,2(1)：18-20
[73]He LN, He S B, Yang J. Protective effect of Tanshinones on primary cultured cortex neurons injury induced by ischemia. Chinese Pharmacological Bulletin.2001; 17(2):214-216
[74]索国玲,唐洪丽等.丹参对幼年大鼠癫痫持续状态学习记忆及海马ChAT、AChE活性的影响.东南大学学报.2007,26(4)：271-274
[75]张旭静,曹奕丰,冯春红.川芎、当归对大鼠血栓形成的影响[J].中国临床药学杂志.2002,11(1)：45
[76]王红,等.葛根及川芎对动物学习记忆的影响.中日友好医院学报.1995,9(4)：191
[77]马娜,朱东海.益智仁提取物对β淀粉样肽致小鼠学习记忆障碍的改善作用及机制分析[J].中国医药导刊.2009,11(7):1175-1176
[78]李克才.益智仁对水蚤寿命的影响[J].生物学杂志.1999,(4)：20.
[79]阳辛凤.利美莲益智与益智酒抗氧化活性的研究[J].华南热带农业大学学报.2001,(3)：20
[80]詹向红,李德新.中医药防治阿尔茨海默病实验研究述要[J].中医药学刊.2004,22(11)：2096
[81]颜乾麟,邢斌.阿尔茨海默病中医治疗目的和方法的拓展.中医杂志.2003,44(10)725
[1]Selkoe D J,The Pathophysiology of Alzheimer's disease. In:Scinto L. F. M., Daf fnerK. R. (Ed.):Early Diagnosis of Alzheimer's Disease. Totowa, New Jersey:Humana Press.2000; 83-104
[2]Lynch C., Mob ley W. Comprehensive Theory of Alzheimer's Disease:The Eeffect of Cholesterol on Membrane Receptor Trafficing. In:Khachaturian Z. S, Mesulam M. M. (Ed.). Alzheimer's Disease:A Compendium of Current Theories. The New York Academy of Sciences, New York.2000; 104-111
[3]Neuroinflammation Working Group. Inflammrtion and Alzheimer's disease. Neuroboil Aging.2000;21 (3):383-421
[4]Abstract from the 9th international conference on Alzheimer's Disease and related disorders. Neurobioiogy of Aging.2004;25(S2):S1-S654
[5]Simons M, Schwarzler F, Lut J E,et,al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer's Disease:A 26-week randomized, placebcontrolled,double-blind trail.Ann Neurol.2002;52 346-350
[6]沈渔邨,李永彤,李格等.Alzheimer性痴呆危险因素的病例对照研究.中华神经精神科杂志.1992,25:284-287
[7]Moreira PI,Zhu X, Lee HG.et al.The (un)blance between metabolic and oxidative abnormalities and cellular compensatory responses in Alzheimer' s Disease. Mechanisms of ageing and development.2006; 127:501-506
[8]马永兴,俞卓伟.北京：现代痴呆学.科学技术文献出版社,2008
[9]Tatebayashi Y, Haque N, Tung Y C, et al.Role of Tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport [J]. J Cell Sci.2004; 117:1653-1663.
[10]Lefebvre T, Ferreira S, Dupont-Wal lois L, et al. Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins-a role in nuclear localization [J].Biochim Biophys Acta.2003; 1619(2):167-176.
[11]Eun Jeoung Lee, Sung Hee Hyun, Jaesun Chun,et al. Regulation of Glycogen Synthase Kinase 3β Functions by Modification of the Small Ubiquitin-Like Modifier. Open Biochem J.2008; 2:67-76.
[12]Berrino F. Western diet and Alzheimer's disease. Epidemiol Prev.2002; 3(2):107-115
[13]Park CR. Cogniitive effects of insulin in the central nervours system. Neurosic Biobehav Rev.2001; 25:311-323
[14]Craft S, Dagogo-Jack SE, Wiethop BV, et al. Effects of hyperglycemia on memory and hormone levels in dementia of the Alzheimer type:a longitudinal study.Behave Neuroscience.1993:107:926-940
[15]盛树力.糖尿病脑病与老年性痴呆.中华内分泌代谢杂志.2001,17：58-59
[16]Webber KM,Raina AK,Marlatt MW, et al.The cell cycle in Alzheimer disease:unique target for neuropharmacology. Mechanisms of Ageing and development.2005; 126:1019-1025
[17]Holmes C, Boche D, Wilkinson D et al. Long-time effects of Abeta(42) in Alzheimer's disease:Follow-up of a randomised,placebo controlled phase Ⅰ trial [J]. Lancet.2008; 372(9634):216
[18]Gomez-Ramos A, Dominguez J, Zafra D, et al. Inhibition of GSK-3 Dependent Tau Phosphorylation by Metals.Curr Alzheimer Res,2006;3(2):123-127.
[19]Le Corre S,Klafki HW,Plesnila N,et al. An inhibitor of tau hyperphosphorylation prevent s severe motor impairment s in tau transgenic mice [J]. Proc Natl Acad Sci USA.2006;103 (25):9673-9678.
[20]Pickhardt M, Gazova Z, von Bergen M, et al. Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired elical filament s in vitro and in cells [J]. JBiol Chem.2005; 280 (5):3628-3635.
[21]Yuzwa, S A; Macauley,M S; Heinonen, J E, et al. A potent mechanism inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo[J].Nat-Chem-Biol.2008; 4(8):483-490
[22]徐剑文,俞昌喜.阿尔茨海默病实验性动物模型的研究进展.国外医学·老年医学分册.2008,29(3)：97-103
[23]徐剑文.PTEN在铝毒性实验性阿尔茨海默病小鼠模型发生发展中的变化.福建医科大学硕士论文,2008
[24]F. Hefti, A. Dravid,J. Hartikka. Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase activity in adult rats with partial septo-hippocampal. Brain Research.1984; 293(2):305-311
[25]Ahmed MM, Hoshino H, Chikuma T, Yamada M, Kato T.Effect of memantine on the levels of glial cells, neuropeptides, and peptide-degrading enzymes in rat brain regions of ibotenic acid-treated alzheimer's disease model. Neuroscience.2004; 126(3):639-649
[26]Moran PM, Higgins LS, Cordell B, Moser PC. Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein. Proc Natl Acad Sci U S A.1995; 92 (12): 5341-5345
[27]Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature.1995; 373 (6514):523-527
[28]Miao J, Xu F, Davis J, Otte-Holler I, Verbeek MM, Van Nostrand WE. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol. 2005; 167 (2):505-515
[29]Richardson, RL, Kim, Eun-Mee, Shephard, RA, Gardiner, T, Cleary, J, O'Hare, E. Behavioural and histopathological analyses of ibuprofen treatment on the effect of aggregated A beta ((1-42)) injections in the rat. Brain Research.2002; 954 (1):1-10
[30]Nabeshima T. Trial to produce animal model of Alzheimer's disease by continuous infusion of beta-amyloid protein into the rat cerebral ventricle. Nihon Shinkei Seishin Yakurigaku Zasshi.1995; 15(5):411-418
[31]Cui X, Zuo P, Zhang Q, Li X, Hu Y, Long J, Packer L, Liu J. Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice:protective effects of R-alpha-lipoic acid. J Neurosci Res.2006; 84(3):647-654-
[32]Kuo H, Ingram DK, Walker LC, Tian M, Hengemihle JM, Jucker M. Similarities in the age-related hippocampal deposition of periodic acid-schiff-positive granules in the senescence-accelerated mouse P8 and C57BL/6 mouse strains. Neuroscience.1996;74 (3):733-740
[33]Poon HF, Farr SA, Thongboonkerd V, Lynn BC, Banks WA, Morley JE, Klein JB, Butterfield DA. Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid:implications for aging and age-related neurodegenerative disorders. Neurochem Int.2005; 46 (2):159-168.
[34]Jong-Hwan Lee, Hea-Nam Hong, Jin-Ok Im, Hong-Seob Byun and Donghou Kim. The formation of PHF-1 and SMI-31 positive dystrophic neurites in rat hippocampus following acute injection of okadaic acid. Neuroscience Letters.2000; 282 (1-2):49-52
[35]Gotz J, Probst A, Spillantini MG, Schafer T, Jakes R, Burki K, Goedert M. Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J. 1995; 14(7):1304-1313.
[36]Jada Lewis, Eileen McGowan, Julia Rockwood, Heather Melrose, Parimala Nacharaju, Marjon Van Slegtenhorst, Katrina Gwinn-Hardy, M. P Murphy, Matt Baker, Xin Yu, Karen Duff, John Hardy, Anthony Corral, Wen-Lang Lin, Shu-Hui Yen, Dennis W. Dickson, Peter Davies, Mike Hutton. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genetics.2000;25:402-405
[37]Blokland A, Jolles J. Spatial learning deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin. Pharmacol Biochem Behav.1993; 44 (2):491-494
[38]Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozo-tocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis.2006; 9(1):13-33
[39]Bennett MC, Rose GM. Chronic sodium azide treatment impairs learning of the Morris water maze task. Behav Neural Biol.1992;58 (1):72-75
[40]Florence AL, Gauthier A, Ponsar C, Van den Bosch de Aguilar P, Crichton RR. An experimental animal model of aluminium overload. Neurodegeneration. 1994; 3(4):315-323.
[41]张章,俞昌喜.褪黑素对侧脑室注射氯化铝致小鼠学习记忆障碍的改善作用及其机制.药学学报.2002,37:682-686
[42]陈贵海,尹世杰,周江宁.突触改变与Alzheimer病发病的关系.中华神经科杂志.2003,36:228-230
[43]BraakH, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl).1991; 82:239-259
[44]KleinWL, Krafft GA, Finch CE. Target ing sma11 Aβ oligomers:the solution to an Alzheimer's disease conundrum? Trends Neurosci.2001; 24:219-224
[45]Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature.200; 416:535-539
[46]Lee HG, Castellani RJ, Zhu XW, et al. Amyloid-β in Alzheimer's disease: the horse or the cart? Pathogenic or protective? Int J Exp Path.2005; 86: 133-138
[47]Baum LW. Sex, hormones, and Alzheimer's disease. J Gerontol A Biol Sci Med Sci.2005; 60:736-743
[48]Khachaturian Z. S. Epilogue:Toward a Comprehensive Theory of Alzheimer' s Disease-Challenge,Caweats,and Parameters. In:Khachaturian Z. S., Mesulam M.M. (Ed.). Alzheimer's Disease:A Compendium of Current Theorise. The New York Academy of Sciences, New York.2000;184-194
[49]蔡琰.老年性痴呆研究进展.国内外医学科学进展.卫生部科技教育司上海市医学科学技术情报研究所.2001,96-99
[50]王奕,金国琴.阿尔茨海默病的“有害网络”.中国老年学杂志.2003,23(2)：128-131
[51]Lefebvre T, Ferreira S, Dupont-Wallois L, et al. Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins-a role in nuclear localization[J]. Biochim Biophys Acta.2003; 1619 (2):167-176.
[52]Liu F, Iqbal K, Grundke-Iqbal I, et al. O-GlcNAcylation regulates phosphorylation of tau:a mechanism involved in alzheimer's disease [J] Proc Natl Acad Sci USA.2004;101:10804-10809.
[53]Dias,W B; Hart,G W.O-GlcNAc modification in diabetes and Alzheimer's disease[J]. Mol-Biosyst.2007;3(11):766-72
[54]Yuzwa, S A;Macauley,M S;Heinonen, J E, et al.A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo[J]. Nat-Chem-Biol.2008; 4(8):483-90.
[55]Yanqiu Deng, Bin Li, Ying Liu, Khalid Iqbal,Inge Grundke-Iqbal, and Cheng-Xin Gong. Dysregulation of Insul in Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain-Implication for Alzheimer's Disease. The American Journal of Pathology.2009; 175(5):6-7
[56]Lee T F, Shiao YJ, Chen C F, et al. Effect of ginseng saponins on beta2amyloid2suppressed acetylcholine release fromrat hippocampal slices[J]. Planta Med.2001; 67(7):634-663.
[57]张均田,刘云,屈志炜,等.人参皂甙Rb1和Rg1对小鼠中枢神经递质和脑内蛋白质合成的影响[J].药学学报,1988,23(1)：12-16.
[58]Sal in K N,McEwen B S, Chao H M, et al. Ginsenoside Rbl regulates ChAT, NGF and trKA mRNA expression in the rat brain[J]. Brain Res Mol Brain Res.1997;47 (122):177-182.
[59]张静,黄天文,陈晓春,宋锦秋,曾育琦.人参皂苷Rg1通过CDK5途径减轻Aβ25235诱导的神经元tau蛋白磷酸化.福建医科大学学报.2008,42(1)：9-10.
[60]李国栋,袁保梅,鄢文海,邢莹.人参皂苷Rb1对内源性Aβ所致小鼠神经细胞Tau蛋白过磷酸化的干预作用.山东医药.2009,49(3)：26-27.
1.ICV-STZ大鼠存在明显的学习记忆障碍及海马神经元超微结构的破坏。
2.复方银思维有明显的改善ICV-STZ拟SAD大鼠空间学习记忆能力的作用。
3.复方银思维改善SAD大鼠学习记忆能力的超微形态学基础可能与保护海马神经元线粒体及轴突内微管结构有关。
[1]Sharma M, Gupta YK.Intracerebroventricular injection of streptozoto-cin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci.2001;68(9):1021-1029
[2]George Paxinos Charles Waston著,诸葛启钏译.The Rat Brain in stereotaxic coordinates (大鼠脑立体定向图谱)[M].北京：人民卫生出版社,2005,第3版
[3]李爱萍,赵慧,李韶,等.不同鼠种在Morris水迷宫学习记忆行为中的种属差异.中国行为医学科学.2005,14(1)：29-31
[4]沈政,林庶芝编著.生理心理学(第二版).北京：北京大学出版社,2007,84-115
[5]ArakiT, SasakiY, Milbrandt J. Increased nuclear NAD+ biosynthesis and SIRT1 activation prevent axonal degeneration [J]. Science,2004; 305:1010-1013
[6]Hung A. J., Stanbury M. G., Shanabrough M, et al. Estrogen, synaptic Plasticity and hypothalamic reproductive aging. ExperimentalGerontology.2003; 38: 53-59
[7]Sergeant N, David J, Champain D, et al. Progressive decrease of amyloid p recursor p rotein carboxy terminal fragments (APP-CTFs), associated with tau pathology stages, in Alzheimer's disease[J]. J Neurochem,2002; 81 (4):663.
[8]Hanger DP, Brion JP. Tau in Alzheimer's disease and Down's syndrome is insoluble and abnormally phosphorylated [J].Biochem J,1991; 275:99-140.
[9]龚成新,王建枝.tau蛋白在老年性痴呆症神经原纤维退行性变中的作用.医学分子生物学杂志.2006,3(3)：163-169
[10]Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Post-translational modifications of tau protein in Alzheimer's disease. J Neural Transm.2005; 112(6): 813-838
[11]王蓉,邵志敏,盛树力.3型糖尿病-散发性老年性痴呆研究的新观点.中华老年多器官疾病杂志.2007,6(1)：17-18
[12]Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3 diabetes?J Alzheimers Dis.2005; 7(1):63-80
[13]Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis.2006; 9 (1):13-33.
[14]RM O'Br ien, RS Streeper, JE Ayala, et al. Insul in-regulated gene expression. Biochem Soc Trans.2001; 29(Pt4):552-558
[15]C. R. Park.Cognitive effects of insulin in the central nervous system Purchase. Neuroscience & Biobehavioral Reviews.2001; 25(4):311-323
[16]Gasparini L, Netzer WJ, Greengard P, Xu H. Does insulin dysfunction play a role in Alzheimer's disease? Trends Pharmacol Sci.2002; 23(6):288-293
[17]盛树力.糖尿病脑病与老年性痴呆.中华内分泌代谢杂志.2001,17:58-59
[18]Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S.Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone:a preliminary study. Am J Geriatr Psychiatry.2005; 13(11):950-958
[19]Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease:follow-up of a randomised, placebo-controlled phase Ⅰ trial. Lancet.2008; 372(9634):216-223.
[20]Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci.2001; 68(9):1021-1029
[21]Shoham S, Bejar C, Kovalev E, Weinstock M. Intracerebroventricular injection of streptozotocin causes neurotoxicity to myelin that contributes to spatial memory deficits in rats. Exp Neurol.2003; 184 (2) :1043-1052
[22]Weinstock M, Shoham S.Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity. J Neural Transm.2004; 111 (3):347-366
[23]Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis.2006;9(1):13-33
[24]Tiwari,-V; Kuhad,-A; Bishnoi,-M; Chopra,-K.Chronic treatment with tocotrienol, an isoform of vitamin E, prevents intracerebroventricular streptozotocin-induced cognitive impairment and oxidative-Nitrosative stress in rats. Pharmacol-Biochem-Behav.2009;93 (2):183-189
[25]Hoyer,-S; Lannert,-H. Long-term effects of corticosterone on behavior, oxidative and energy metabolism of parietotemporal cerebral cortex and hippocampus of rats:comparison to intracerebroventricular streptozotocin. J-Neural-Transm.2008;115 (9):1241-1249
[26]Tauheed Ishrat, Kehkashan Parveen, Mohd. Moshahid Khan, Gulrana Khuwaja, M. Badruzza-man Khan, Seema Yousuf, Ajmal Ahmad, Pallavi Shrivastav and Fakhrul Islam.Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer's type. Brain Research.2009; 1281:117-127
[27]Blokland A, Jolles J. Spatial learning deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin. Pharmacol Biochem Behav.1993;44 (2):491-494
[28]Roman Duelli, Helmut Schrock, Wolfgang Kuschinsky, Siegfried Hoyer. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. International Journal of Developmental Neuroscience.1994; 12 (8):737-743
[29]Lannert H, Hoyer S.Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998; 112(5):1199-1208
[30]Hoyer S, Lee SK, Loffler T, Schliebs R. Inhibition of the neuronal insulin receptor. An in vivo model for sporadic Alzheimer disease? Ann N Y Acad Sci.2000; 920:256-258
[31]Hoyer S. The brain insulin signal transduction system and sporadic (typeⅡ) Alzheimer disease:an update. J Neural Transm.2002;109(3):341-360
[32]G J Biessels,F-E De Leeuw, J Lindeboom,et al. Increased cortical atrophy in patients with Alzheimer disease and type2 diabetes mellitus. J Neurol Neurosurg Psychiatry.2006; 77:304-307
[33]WZ Chu and CY Qian. Expressions of Abeta1-40, Abeta1-42, tau202, tau396 and tau404 after intracerebroventricular injection of streptozotocin in rats.Di Yi Jun Yi Da Xue Xue Bao.2005; 25 (2):168-170
[34]Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis.2006;9 (1):13-33
[35]Sonkusare S, Srinivasan K, Kaul C, Ramarao P.Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats. Life Sci.2005; 77(1):1-14
[36]Hoyer S.Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol.2004; 490 (1-3):115-125
[37]Duelli R, Schrock H, Kuschinsky W, Hoyer S. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci.1994;12(8):737-743
[38]Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998; 112(5):1199-1208
[49]Shoham S, Bejar C, Kovalev E, Schorer-Apelbaum D, Weinstock M. Ladostigil prevents gliosis, oxidative-nitrative stress and memory deficits induced by intracerebroventricular injection of streptozot-ocin in rats. Neuropharmacology.2007;52 (3):836-843
[40]Tuppo EE, Arias HR. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol.2005; 37(2):289-305
[41]Finch CE. Neurons, glia, and plasticity in normal brain aging. Neurobiol Aging.2003; 24 Suppl 1:S123-127, discussion S131
[42]Prickaerts J, Fahrig T, Blokland A. Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i. c. v. injection of streptozotocin:a correlation analysis. Behav Brain Res. 1999; 102(1-2):73-88
[43]Rodrigues L, Biasibetti R, Swarowsky A et al. Hippocampal alterations in rats submitted to streptozotocin-induced dementia model are prevented by aminoguanidine. J Alzheimers Dis.2009; 17(1):193-202
[44]Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? J Alzheimers Dis.2005; 7(1):63-80.
[45]Hellweg R, Nitsch R, Hock C, Jaksch M, Hoyer S. Nerve growth factor and choline acetyltransferase activity levels in the rat brain following experimental impairment of cerebral glucose and energy metabolism. J Neurosci Res.1992; 31 (3):479-486
[46]符鹏程,杨期东等.脑室注射链脉佐菌素对大鼠空间学习记忆能力、海马CAI区神经元的数量和海马突触素表达的影响.神经解剖学杂志.2009,25(3)：249-254
[47]符鹏程.吡格列酮对AO大鼠记忆障碍的作用及其机制的研究.中南大学湘雅医院博士研究生论文.2009
[48]Moser MB, Moser EI, Forrest E, Andersen P, Morris RG. Spatial learning with a minislab in the dorsal hippocampus. Proc Natl Acad Sci U S A. 1995;92 (21):9697-9701
[49]Kucukatay V, Balkan S, Yara N, Yargicolu P, Aar A. The effect of pergolide on cognitive performance of young and middle-aged rats. Int J Neurosci.2002; 112(9):1027-1036
[50]张均田.人参皂苷Rg1的促智作用机制对神经可塑性和神经发生的影响[J].药学学报.2005,40(5)：385-388
1.ICV-STZ大鼠大脑皮层与脑能量代谢及线粒体功能相关的SDH、COX、 Na+-K+-ATPase酶活性低下,且大脑皮层ChAT活性低下,而AchE活性增高,存在明显的脑能量代谢障碍及胆碱能系统紊乱。
2.复方银思维能显著提高ICV-STZ拟SAD大鼠皮层SDH、COX、Na+-K-ATPase的活性,从而改善脑组织能量代谢及线粒体功能。
3.复方银思维能够提高ICV-STZ拟SAD大鼠大脑皮层ChAT活性,同时使得AchE活性下降,从而调节胆碱能神经递质的合成与代谢平衡。
[1]Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci.2001; 68 (9):1021-1029
[2]George Paxinos Charles Waston著,诸葛启钏译.The Rat Brain in stereotaxic coordinates(大鼠脑立体定向图谱)[M].北京：人民卫生出版社,2005,第3版
[3]王琴,黄慧玲,刘锐等.亚低温对急性颅脑创伤大鼠线粒体呼吸链酶活性的影响.天津医药.2000,36(7)：524-526
[4]Blass J P, Gibson G E, Hoyer S. The role of the metabolic lesion in Alzheimer' s Disease. J Alzheimer's Dis.2002; 4:225-232
[5]Blass J P. The Mitochondrial spiral An adequate cause of dementia in the Alzheimer's syndrome. In:Khachaturian Z. S.,Mesulam M. M. (Ed.), Alzheimer' s Disease:A Compendium of Current Theories. The New York Academy of Sciences, New York, ANN N Y ACAD SCI.2000;924:170-183
[6]Papa S. Mitochondrial oxidative phosphorylation changes in the life span: Molecular aspects and physiological implications [J]. Biochem Biophys Acta, 1996; 1276 (2):87-105.
[7]S Hoyer. Memory function and brain glucose metabolism. Pharmacopsychiatry. 2003; 36 (Suppll):S62-S67
[8]Torlinska T, Grochowalska A. Age-related changes of NA+-K+-ATPase, Ca+2-ATPase and Mg+2-ATPase activities in rat brain synaptosomes. J Physiol Pharmacol,2004;55 (2):457
[9]Gil-Bea F J, Garcia-AllozaM, DominguezJ, et al. Evaluation of cholinergic markers in Alzheimer's disease and in a modelof cholinergic deficit [J]. Neurosci Lett,2005;375:37
[10]Duelli R, Schrock H, Kuschinsky W, Hoyer S. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci.1994; 12(8):737-743
[11]Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998; 112(5):1199-1208
[12]Tauheed Ishrat, M. Badruzzaman Khan, Md. Nasrul Hoda, Seema Yousuf, Muzamil Ahmad, Mubeen A. Ansari, Abdullah S. Ahmad and Fakhrul Islam. Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats. Behavioural brain research.2006; 171(1):9-16.
[13]Tauheed Ishrat, Kehkashan Parveen, Mohd. Moshahid Khan, Gulrana Khuwaja, M. Badruzzaman Khan, Seema Yousuf, Ajmal Ahmad, Pallavi Shrivastav and Fakhrul Islam. Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer's type. Brain Res.2009; 1281:117-127.
[14]Swapn.il Sonkusare, Krishnamoorthy Srinivasan, Chamanlal Kaul and Poduri Ramarao. Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats. Life Sci. 2005; 77(1):1-14.
[15]Liu M, Zhang J.Effects of ginsenoside Rbl and Rgl on synaptosomal free calcium level, ATPase and calmodul in in rat hippocampus. Chin Med J (Engl). 1995; 108(7):544-547. 存在tau的异常O-GlcNAc糖基化修饰。
2.复方银思维能明显提高ICV-STZ拟SAD大鼠海马组织tau蛋白的O-GlcNAc糖基化修饰水平。
3.复方银思维能显著提高SAD模型大鼠海马OGT的表达,降低O-GlcNAcase的表达,从而对tau蛋白O-GlcNAc糖基化修饰产生正向作用。
[1]Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci.2001; 68(9):1021-1029
[2]George Paxinos Charles Waston著,诸葛启钏译.The Rat Brain in stereotaxic coordinates (大鼠脑立体定向图谱)[M].北京：人民卫生出版社,2005,第3版
[3]龚成新,王建枝.tau蛋白在老年性痴呆症神经原纤维退行性变中的作用.医学分子生物学杂志,2006;3(3)：163-169
[4]Tatebayashi Y, Haque N, Tung Y C, et al.Role of Tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport [J]. J Cell Sci,2004; 117:1653-1663.
[5]Ebneth A, Godemann R, Stamer K, et al. Over expression of Tau protein inhibits kinesin-dependent trafficking of vesicles,mitochondria and endop lasmic reticulum:implications for Alzheimer's disease[J]. J Cell Biol,1998; 143: 777-7941
[6]Hua Q, He R Q, Haque N, et al. Microtubule associated p rotein tau binds to double-stranded but not single-stranded DNA[J]. CellMol Life Sci,2003; 60:413-421
[7]Bhaskar K, Yen S H, Lee G. Disease related modifications in tau affect the interaction between fyn and tau [J]. J Biol Chem,2005; 280 (42):35119-35125
[8]Iqbal K, Grundke-Iqbal I.Discoveries of tau,abnormallly Hyperphosp-horylated tau and others of neurofibrillary degeneration:a personal historical perspective.J Alzheimer's Dis.2006; 9(3 Suppl):219-242
[9]Utton MA, Noble WJ, Hill JE, et al. Molecular motors implicated in the axonal transport of tau and alpha-synuclein. J Cell Sci.2005; 118:4645-4654
[10]Kepke E, Tung Y C, Sha Ikh S, et al. Microbutule associated protein tau: abnormal phosphorylation of a non-paired helical filament pool in alzheimer disease [J].J Biol Chem,1993;268:24374-24384
[11]第五永长,田金洲.Tau蛋白磷酸化及O-GlcNAc糖基化修饰与阿尔茨海默病.中风与 神经疾病杂志.2010,27(3)：111
[12]C. R. Torres and G. W. Hart, J. Biol.Chem.,1984; 259,3308-3317
[13]N. E. Zachara and G. W. Hart, Biochim. Biophys. Acta,2006; 1761,599-617.
[14]D. C. Love and J. A. Hanover, Sci.STKE,2005; 2005, re13.
[15]K. Vosseller, J. C. Trinidad, R. J. Chalkley, C. G. Specht, A. Thalhammer, A. J. Lynn, J.O. Snedecor, S. Guan, K. F. Medzihradszky, D. A. Maltby, R. Schoepfer and A. L. Burlingame, Mol.Cell. Proteomics,2006; 5,923-934.
[16]N. Khidekel, S. B. Ficarro, E. C. Peters and L. C. Hsieh-Wilson, Proc. Natl. Acad. Sci. U. S. A.,2004; 101,13132-13137.
[17]A. Nandi, R. Sprung, D. K. Barma, Y. Zhao, S. C. Kim, J. R. Falck and Y. Zhao, Anal. Chem.,2006; 78,452-458.
[18]Z. Wang, A. Pandey and G. W. Hart, Mol. Cel 1. Proteomics,2007; 6,1365-1379.
[19]Dias,W B; Hart,G W.O-GlcNAc modification in diabetes and Alzheimer's disease[J]. Mol-Biosyst.2007; 3(11):766-772
[20]Hart G W. Dynamic 0-linked glycosylation of nuclear and cytoskeletal proteins [J]. Annu Biochem,1997; 66(1):315-335
[21]Hoyer S. Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease:therapeutic implications [J]. Adv Exp Med Biol,2004; 541:135-152
[22]Gong C X, Liu F, Grundke-Iqbal I, et al. Impaired brain glucose metabolism leads to alzheimer neurofibrillary degeneration through a decrease in tau o-GlcNAcylation[J].J Azheimer's Dis,2006; 9 (1):1-12.
[23]Hart G W, Greis K D, Dong L Y, et al.0-linked N-acetylglucosamine:the "yin-yang" of Ser/Thr phosphorylation Nuclear and cytoplasmic glycosy-lation[J]. Adv Exp Med Biol,1995; 376:115-23
[24]Liu F, Iqbal K, Grundke-Iqbal I, et al. O-GlcNAcylation regulates phosphorylat ion of tau:a mechanism involved in alzheimer's disease [J] Proc Natl Acad Sci USA,2004; 101:10804-10809.
[25]Planel E,Miyasaka T,Launey T,et al. Alterations in glucose metabolism induce hypothermia leading to tauhyperphosphorylation through different-ial inhibition of kinase and phosphatase activities:implications for Alzheimer's disease[J]. J Neurosci,2004; 24 (10):2401-2411
[26]Quinn CM, kagedal K, Terman A, et al. Induction of fibroblast apol ipoprotein E expression during apoptosis, starvation-induced growth arrest and mitosis[J]. Biochem J,2004; 37 (3):753-761
[27]Yanqiu Deng, Bin Li, Ying Liu, Khalid Iqbal, Inge Grundke-Iqbal, and Cheng-Xin Gong. Dysregulation of Insulin Signaling, Glucose Transporters, 0-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain-Implication for Alzheimer's Disease. The American Journal of Pathology.2009; 175(5):6-7
[28]Yuzwa, S A; Macauley, M S; Heinonen, J E, et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo[J].Nat-Chem-Biol.2008; 4(8):483-90
[29]Tallent,M K; Varghis,N; Skorobogatko, Y, et al. In Vivo Modulation of 0-GlcNAc Levels Regulates Hippocampal Synaptic Plasticity through Interplay with Phosphorylation[J]. J-Biol-Chem.2009; 284(1):174-81
[30]Xiaoyong Yang, Pat P. Ongusaha, Philip D. Miles, Joyce C. Havstad, Fengxue Zhang, W. Venus So, Jeffrey E. Kudlow, Robert H. Michell, Jerrold M. Olefsky, Seth J. Field & Ronald M. Evans. Phosphoinosit ide signal ling links O-GlcNAc transferase to insulin resistance. Nature.2008; 451:964-969
[31]宋丽娜,王京兰,钱小红,蔡耘.O-GlcNAc修饰蛋白质的生理功能和研究方法.生命的化学.2007,27(1)：14-16
[32]Khidekel N et al. Proc Natl Acad Sci USA,2004;101 (36):13132-13137
[33]Comer FI et al. Anal Biochem,2001; 293 (2):169-177
[34]Nandi A et al. Anal Chem,2006; 78(2):452-458
[35]Fei Liu, Jianhua Shi, Hitoshi Tanimukai, Jinhua Gu, Jianlan Gu, Inge Grundke-Iqbal, Khalid Iqbal and Cheng-Xin Gong. Reduced O-GlcNAcyla-tion links lower brainglucose metabolism and tau pathology in Alzheimer' s disease. Brain.2009; 132(7):1820 1832.
1. ICV-STZ大鼠海马组织tau蛋白重要位点Thr 231和Ser422的磷酸化P-Thr 231、P-Ser422表达增多,与实验三中脑组织tau的O-GlcNAc糖基化修饰水平呈反向关联,模型大鼠海马组织存在tau蛋白的异常磷酸化。
2.复方银思维能显著减少ICV-STZ拟SAD模型大鼠海马组织P-Thr 231、P-Ser422的表达,从而抑制tau蛋白在重要位点的异常过度磷酸化,防止tau毒性和进一步的纤维状结构形成。
[1]Gong CX, Liu F, Grundke-Iqbal I, Iqbal K.Post-translational modifications of tau protein in Alzheimer's disease. J Neural Transm.2005; 112 (6):813-838
[2]龚成新,王建枝.tau蛋白在老年性痴呆症神经原纤维退行性变中的作用.医学分子生物学杂志.2006；3(3)：163-169
[3]Cheng Xin Gong, Fei Liu, Inge Grundke-Iqbal, et al. Dysregulation of Protein Phosphorylation/Dephosphorylation in Alzheimer's Disease:A Therapeutic Target [J]. J Biomed Biotechnol.2006; 2006(3):31825
[4]Patrice Delobel, Isabelle Lavenir, Graham Fraser,et al.Analysis of Tau Phosphorylation and Truncation in a Mouse Model of Human Tauopathy Analysis of Mouse Tauopathy[J]. Am J Pathol. 2008;172 (1):123-131
[5]Liu F, Grundke-Iqbal I, Iqbal K, Gong CX.Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci.2005; 22 (8):1942-1950
[6]Tanaka T, Zhong J, Iqbal K, et al.The regulation of phosphorylation of tau in sy5y neuroblastoma cells:the role of p rotein phosphatases [J]. FEBS Lett.1998; 426(2):248-254.
[7]Bennecib M, Gong CX, Grundke-Iqbal I, Iqbal K.Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356. FEBS Lett.2001; 490 (1-2):15-22
[8]Pei J J, Gong C X, Anw, et al. Okadaic-acid-induced inhibition of p rotein phosphatase2a produces activation of mitogen-activated protein kinases erk1/2, mek1/2, and p70 s6, similar to that in alzheimer's disease[J]. Am J Pathol.2003; 163:845-858.
[9]Liu F, Iqbal K, Grundke-Iqbal I, et al.O-GlcNAcylation regulates phosphorylation of tau:a mechanism involved in alzheimer's disease [J]. Proc Natl Acad Sci USA.2004;101:10804-10809.
[10]Robertson L A, Moya KL, Breen K C. The potential role of tau p rotein o-glycosylation in alzheimer's disease [J].J Alzheimer's Dis.2004; 6 (5):489-495.
[11]Gong CX, Liu F, Grundke-Iqbal I, et al. Impaired brain glucose metabolism leads to alzheimer neurofibrillary degeneration through a decrease in tau o-GlcNAcylation[J]. J Azheimer's Dis.2006; 9 (1):1-12.
[12]Yuzwa,S A; Macauley, M S; Heinonen, J E, et al. A potent mechanism-inspired 0-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo[J]. Nat-Chem-Biol.2008; 4(8):483-90
[13]Fei Liu, Jianhua Shi, Hitoshi Tanimukai, Jinhua Gu, Jianlan Gu, Inge Grundke-Iqbal, Khalid Iqbal and Cheng-Xin Gong. Reduced 0-GlcNAcyla-tion links lower brainglucose metabolism and tau pathology in Alzheimer' s disease. Brain.2009; 132(7):1820 1832.
[14]Harada A, Oguchi K, Okabe S, et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein [J].Nature.1994; 369: 488-491
[15]Alonso A, Del C, Grundke-Iqbal I.Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules[J] Nature Med.1996; 2:783-787
[16]Alonso A, Del C, Grundke-Iqbal I, et al. Abnormal phosphorylation of tau and the mechanism of alzheimer neurof ibrillary degeneration:sequestration of microtubule-associated proteinsl and 2 and the disassembly of micro-tubules by the abnormal Tau[J]. Proc Natl Acad Sci USA.1997;94:298-303
[17]Hern a ndez F, Borrell J, Guaza C, Avila J, Lucas JJ. Spatial learning deficit in transgenic mice that conditionally over-express gsk-3beta in the brain but do not form tau filaments [J]. J Neurochem.2002; 83 (6): 1529-153
[18]Lee VM, Kenyon TK, Trojanowski JQ. Transgenic animalmodels of tauopathies [J].Biochim Biophys Acta.2005; 1739 (223):251-259
[19]Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Post-translational Modifications of tau protein in Alzheimer's disease. J Neural Transm.2005; 112 (6): 813-838
[20]Sengupta A, Kabat J, Novakm, et al. Maximal inhibition of tau binding tomicrotubules requires the phosphorylation of tau at both thr 231 and Ser 262 [J]. Neurobiol Ageing.1998; (19S):S124-524.
[21]Schneider A, B iernat J, Von Bergenm, et al. Phosphorylation that detaches tau p rotein from microtubules (ser262, ser214) also p rotects it against aggregation into alzheimer paired helical filaments[J]. Biochemistry. 1999; 38:3549-3558.
[22]Alonso A, Del C, Mederl Yova A, et al. Promotion of hyperphosphorylation by frontotemporal dementia taumutations[J]. J Biol Chem.2004; 279:34878-34881.
[23]Abraha A, Ghoshal N, Gamblin TC, Cryns V, Berry RW, Kuret J, Binder LI. C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease.J Cell Sci.2000; 113 (Pt21):3737-3745
[24]Haase C, Stieler J, Arend T T, et al. Pseudophosphorylation of tau p rotein alters its ability for self-aggregation[J]. J Neurochem.2004; 88:1509-1520.
[25]Ferrar IA, Hoerndl I F, Baech I T, et al. Beta-amyloid induces paired hel ical f ilament-like tau f ilaments in tissue culture [J]. J Biol Chem.2003; 278:40162-40168.
[26]严冬梅,李洪.磷酸化蛋白质检测技术研究进展.泸州医学院学报.2006,29(5)：460-461
[27]Goodman T, Schulenberg B, Steinberg TH, et al. Detection of phosphoproteins on electroblot membrarles using a small-molecule organic fluorophore [J]. Electrophoresis.2004; 25(15):2533
[28]Yanqiu Deng, Bin Li, Ying Liu, Khalid Iqbal,Inge Grundke-Iqbal, and Cheng-Xin Gong. Dysregulation of Insulin Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain-Implication for Alzheimer's Disease. The American Journal of Pathology.2009; 175(5):6-7
[29]Buerger K, Teipel S J, Zinkowski R, et al.CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MMI subjects [J]. Neurology.2002; 59 (4); 627-629.
[1]Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin like growth factor expression and signaling mechanisms in Alzheimer's disease is this type 3 diabetes? [J] J Alzheimer's Dis.2005; 7:63-80.
[2]Lester-Coll N, Rivera EJ, Soscia SJ, et al. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease[J]. J Alzheimers Dis.2006; 1:13-33
[3]Basu R, Breda E, Oberg AL, et al. Mechanisms of the age associated deterioration in glucose tolerance:contribution of alterations in insulin secretion, action,and clearance [J]. Diabetes.2003;52:1738-1745
[4]Basu R, Man CD, Campioni M, et al. Effects of age and sex on postprandial glucose metabolism:differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction[J]. Diabetes.2006; 55: 2001-2014
[5]赵路清,王鲁宁.胰岛素及胰岛素-胰岛素受体信号通路异常与阿尔茨海默病研究进展[J].中华老年医学杂志.2007,26(2)：152
[6]Watson GS, Peskind ER, Asthana S, et al. Insulin increases CSF Ab42 levels in normal older adults[J]. Neurology.2003; 60:1899-1903
[7]Zhao LX, Bruce T, Takashi M, et al. Insul in-degrading enzyme as a downstream target of insulin receptor signaling cascade; implication for Alzheimer's disease intervention[J].J Neurosci.2004; 24:11120-11126
[8]Suzanne Craft. Insulin Resistance and Alzheimer's Disease Pathogenesis: Potential Mechanisms and Implications for Treatment[J]. Current Alzheimer Research.2007; 4,147-152
[9]Skeberdis VA, Lan J, Zhang X, et al. Insulin promotes rapid delivery of N-methyl-D-asparate receptors to the cell surpace by exocytosi [J].Proc Natl Acad Sci USA.1998; 3561-3566
[10]Byrne JH. Learning and memery:basic mechanisms. In:Squire LR, Bloom FE, McConnell SK, etal. eds.Fundamental neuroscience.San Diego CA:Academic Press.2003; 1276-1298.
[11]Schubert M, Brazil DP, Burks DJ, et al. Insulin receptor substrate22 deficiency impairs brain growth and promotes tau phosphorylation[J]. J Neurosci.2003; 23:7084-7092
[12]Gasparini L, Netzer WJ, Greengard P, et al. Does insulin dysfunction play a role in Alzheimer's disease? [J]. Trends Pharmacol Sci.2002; 23:288-293
[13]Castillo DV, Figueroa-Guzman Y, Escobar ML. Brain-derive neurotrophic factor enhance conditioned taste aversion retention [J].Brain Res.2006; 1067:205-255.
[14]von Bohlen und Halbach O, Krause S, Medina D,et al, Regional and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies[J].Biol Psychiatry.2006;59: 793-800
[15]Li ZG, Zhang W, Grunberger G, et al. Hippocampal neuronal apoptosisin Type 1 diabetes[J]. Brain Res.2002; 946:221-231.
[16]王蓬文,杨芳,盛树力,等.胰岛素样生长因子受体-1在糖尿病小鼠脑内的分布[J].神经解剖学杂志.2002；18(2)：127-130.
[17]Watson GS, Cholerton BA, Reger MA, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone [J]. Am J Geriatr Psychiat.2005;13:950-958.
[18]J Am Med Assoe[J].2004; 292:2237-2242
[19]Vlassara H, Palace MR. Glycoxidation:the menace of diabetes and aging [J]. Mt Sinai J Med.2003; 70:232-241
[20]Wada-Isoe K, Wakutani Y, Urakami K et al.Elavated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients[J]. Acta Neurol Scand.2004; 110(2):124-127
[21]Jia JP,Meng R, Sun YX et al. Cerebrospinal fluid tau, Abetal-42 and inflammatory cytokines in patients with Alzheimer's disease and vascular dementia[J].Neurosci Lett.2005; 383(12):12-16
[22]Van Exel E,Gussekloo J, Remarque EJ. Ineraction of atherosclerosis and inflammation in elderly subjects with poor cognitive function [J]. Neurology.2003; 61(12):1605-1701
[23]Tarkowski E,Tullberg M, Fredman P et al. Corretation between intrathecal sulfatide and TNF-alpha levels in patients with vascular dementia[J]. Dement Geriatr Cogn Disord.2003; 15 (4):207-211
[24]Bowler J V. Vascular cognitive impairment advances in stroke 2003 [J]. Journal of the American Heart Association,2004; 35:386-388.
[25]Fouyas IP,Kelly PA,Ritchie IM, et al. Cerebrovascular responses to pathophysiological insulin in diabetic rats[J].J Clin Neurosci 2003; 10:88-91
[1]Riley KP, Snowdon DA, MarkesberyWR. Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study [J]. Ann Neurol.2002; 51 (5):567-577.
[2]Gong C X, Liu F, Iqbal K, et al. Post-translational modifications of tau protein in Alzheimer's disease[J]. J Neural Transm.2005; 112(6):813-838
[3]Dong Lei, Zhou Wen-Xia, Zhang Yong-Xiang.Abnormal post-translational modification of Tau protein and Alzheimer's disease[J]. Bulletin of the Academy of Military Medical Sciences.2006; 20 (1):76-79
[4]Gold M. Tau therapeutics for Alzheimer's disease:the promise and the challenges [J]. JMol neurosci.2002;19 (3):331-4
[5]Liu F, Iqbal K, Grundke-Iqbal I, et al. O-GlcNAcylation regulates phosphorylation of tau:a mechanism involved in alzheimer's disease [J] Proc Natl Acad Sci USA.2004; 101:10804-10809
[6]Lef ebvre T, Ferreira S, Dupont-Wallois L, et al. Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins-a role in nuclear localization[J]. Biochim Biophys Acta.2003; 1619(2):167-176.
[7]Tatebayashi Y, Haque N, Tung Y C, et al.Role of Tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport [J].J Cell Sci.2004; 117:1653-1663.
[8]Ebneth A, Godemann R, Stamer K, et al. Overexp ress ionof Tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria and endop lasmic reticulum:imp lications for Alzheimer's disease[J]. J Cell Biol.1998; 143(3):777-794
[9]Hua Q, He R Q, Haque N, et al. Microtubule associated p rotein tau binds to double-stranded but not single-stranded DNA[J]. CellMol Life Sci.2003; 60: 413-421.
[10]Bhaskar K, Yen S H, Lee G. Disease related modifications in tau affect the interaction between fyn and tau [J]. J Biol Chem.2005;280 (42):35119-35125.
[11]Hoffmann R, Leevm, Leight S, et al. Unique Alzheimer'sdisease paired helical filament specific ep itopes involve double phosphorylation at specific sites[J]. Biochemistry.1997; 36:8114-8124.
[12]Bussiere T, Hof P R, Maill lot C, et al. Delacourte a phosphorylated serine422 on tau p roteins is a pathological ep itope found in several diseases with neurofibrillary degeneration [J]. Acta Neuropathol (Berl). 1999; 97:221-230.
[13]Kepke E, Tung Y C, Sha Ikh S, et al. Microbutule associated protein tau: abnormal phosphorylation of a non2paired helical filament pool in alzheimer disease [J]. J Biol Chem.1993;268:24374-24384.
[14]Sengupta A, Kabat J, Novakm, et al. Maximal inhibition of tau binding tomicrotubules requires the phosphorylation of tau at both thr 231 and Ser 262 [J]. Neurobiol Aging.1998; (19S):S124-524.
[15]Schneider A, B iernat J, Von Bergenm, et al. Phosphorylation that detaches tau p rotein from microtubules (ser262, ser214) also p rotects it against aggregation into alzheimer paired helical filaments[J]. Biochemistry. 1999; 38:3549-3558.
[16]Alonso A, Del C, Mederl Yova A, et al. Promotion of hyperphosphorylation by frontotemporal dementia taumutations[J]. J Biol Chem.2004; 279: 34878-34881.
[17]Abraha A, Ghoshal N, Gambl In T C, et al. C-terminal inhibition of tau assembly in vitro and in alzheimer's disease [J]. J Cell Sci.2000; 113: 3737-3745.
[18]Haase C, Stieler J, Arend T T, et al. Pseudophosphorylation of tau p rotein alters its ability for self-aggregation[J]. J Neurochem.2004;88:1509-1520.
[19]Ferrar IA, Hoerndl I F, Baech I T, et al. Beta-amyloid induces paired helical filament-like tau filaments in tissue culture[J]. J Biol Chem. 2003;278:40162-40168.
[20]Hernandez F, Borrell J, Guaza C, et al.Spatial learning deficit in transgenic mice that conditionally over-exp ress gsk-3beta in the brain but do not form tau filaments [J]. J Neurochem.2002; 83:1529-1533.
[21]Lee V M Y, Kenyon T K, Trojonowski J Q1 Transgenic animalmodels of tauopathies[J]. Biochim Biophys Acta.2005; 1739 (223):251-259.
[22]Cheng Xin Gong, Fei Liu, Inge Grundke-Iqbal, et al. Dysregulation of Protein Phosphorylation/Dephosphorylation in Alzheimer's Disease:A Therapeutic Targe [J]. J Biomed Biotechnol.2006; 2006 (3):31825.
[23]Patrice Delobel, Isabelle Lavenir, Graham Fraser,et al. Analysis of Tau Phosphorylation and Truncation in a Mouse Model of Human Tauopathy Analysis of Mouse Tauopathy[J]. AJP January.2008; 172 (1),123-131
[24]Johnson G V, Stoothoffw H. Tau phosphorylation in neuronal cell function n dysfunction[J]. J Cell Sci.2004;117:5721-5729.
[25]Liu F, Grundke-Iqbal I, Iqbal K, et al. Contributions of protein phosph-atasesppl, pp2a, pp2b and pp5 to the regulation of tau phosphorylation [J]. Eur J Neurosci.2005; 22:1942-1950.
[26]Tanaka T, Zhong J, Iqbal K, et al.The regulation of phosphorylation of tau in sy5y neuroblastoma cells:the role of p rotein phosphatases [J]. FEBS Lett.1998; 426:248-254.
[27]Bennecib M, Gong C X, Grundke-Iqbal I, et al. Inhibition of PP-2A up regulates camkii in rat forebrain and induces hyperphosphorylation of tau at ser 262/356 [J].FEBS Lett.2001; 490:15-22.
[28]Pei J J, Gong C X, Anw, et al. Okadaic-acid-induced inhibition of p rotein phosphatase2a produces activation of mitogen-activated protein kinases erkl/2, mekl/2, and p70 s6, similar to that in alzheimer's disease[J]. Am J Pathol.2003; 163:845-858.
[29]Robertson L A, Moya KL, Breen K C. The potential role of tau p rotein o-glycosylation in alzheimer's disease [J]. J Alzheimer's Dis.2004; 6 (5): 489-495.
[30]Gong CX, Liu F, Grundke-Iqbal I, et al. Impaired brain glucose metabolism leads to alzheimer neurofibrillary degeneration through a decrease in tau o-GlcNAcylation[J].J Azheimer's Dis.2006; 9 (1):1-12.
[31]Hart G W. Dynamic 0-linked glycosylation of nuclear and cytoskeletal proteins [J]. Annu Biochem.1997; 66(1):315-335
[32]Hoyer S. Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease:therapeutic implications[J]. Adv Exp Med Biol.2004; 541:135-152
[33]Minoshima S, Frey K A, Koeppe R A, et al. A diagnostic approach in Alzheimer' s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET[J]. J Nucl Med.1995; 36 (7):1238-1248
[34]Hart G W, Greis K D, Dong L Y, et al.0-linked N-acetylgluc-osamine:the "yin-yang" of Ser/Thr phosphorylation Nuclear and cytoplasmic glycosy-lation[J]. Adv Exp Med Biol.1995; 376:115-123
[35]Planel E,Miyasaka T, Launey T, et al. Alterations in glucose metabolism induce hypothermia leading to tauhyperphosphorylation through different-tial inhibition of kinase and phosphatase activities:implications for Alzheimer's disease[J]. J Neurosci.2004; 24 (10):2401-2411
[36]Quinn CM, kagedal K, Terman A, et al. Induction of fibroblast apolipoprotein E expression during apoptosis, starvation-induced growth arrest and mitosis[J]. Biochem J.2004; 378 (3):753-761.
[37]石俊,李旭,卢芬.饥饿对小鼠脑中tau蛋白磷酸化和O-GlcNAc糖基化的影响[J].生物化学与生物物理进展.2006;33(7)：647-652.
[38]Liu Y, Liu F, Iqbal K, et al. Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer's disease [J]. FEBS Lett.2008; 582 (2):359-364.
[39]Dias,W B; Hart,G W.O-GlcNAc modification in diabetes and Alzheimer's disease[J]. Mol-Biosyst.2007; 3(11):766-772
[40]Tallent,M K; Varghis,N; Skorobogatko, Y,et al. In Vivo Modulation of O-GlcNAc Levels Regulates Hippocampal Synaptic Plasticity through Interplay with Phosphorylation[J]. J-Biol-Chem.2009; 284(1):174-181
[41]Yuzwa, S A; Macauley,M S; Heinonen, J E, et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo[J]. Nat-Chem-Biol.2008; 4(8):483-490
[2]Alzheimer's-Association.2009 Alzhemier's disease facts and figures. Alzhemiers-Dement.2009; 5(3):234-70
[3]Zhang ZX, Zahner GE, Roman GC, et a.l. Dementia subtypes in China: prevalence in Beijing, Xian, Shangha, i and Chengdu. Arch Neuro.2005; 62:447-453.
[4]Ferri CP, Prince M, Brayne C, et a.l. Global prevalence of dementia: a Delphi consensus study. Lancet.2005; 366:2112-2117.
[5]Webber KM,Raina AK,Marlatt MW,et al.The cell cycle in Alzheimer disease:unique target for neuropharmacology. Mechanisms of Ageing and Development.2005; 126:1019-1025
[6]CsermelyP, Agoston V, PongorS. The effieiency of multitarget drugs:the network approach might help drug design[J]. Trends pharmacol Sci.2005; 26 (4) 178-182.
[7]中华全国中医学会老年医学会.老年呆病的诊断辨证分型及疗效评定标准(讨论稿)[J].中医杂志.1991,(2):56-57
[8]谢娟.基于数理统计的老年期痴呆方组方配伍规律研究.南京中医药大学博士学位论文.2009
[9]王晓林,巴哈尔·哈德尔.明清时期治疗老年性痴呆的用药规律.光明中医.2010,25(5)：749
[10]刘维宾,刘维政.历代运用益智方药规律的探讨.江西中医药.2005,36(8):62-63
[11]魏翠柏,田金洲,贾建平.老年痴呆中医病因病机理论的认识与思考[J].中华中医药杂志.2005,20(8)：496-497
[12]王永炎,严世芸.实用中医内科学(第二版)上海科技出版社,2009:455-456
[13]余锐,肖飞,李晓光,等.去痴灵脂溶性提取物血清抑制M146L细胞分泌β淀粉样蛋白[J].中国新药杂志.2006,15(13):1061
[14]张建民,胡愉,王红,等.中药复方CHP Ⅱ对PDAPP转基因小鼠脑组织病变的影响[J].解剖学报.2004,35(6)：622
[15]张婷,董克礼.益智健脑颗粒对阿尔茨海默病患者脑脊液β淀粉样蛋白含量的影响[J].中国老年学杂志.2007,27(6):1080
[16]田金洲,朱爱华,钟剑.金思维治疗社区轻度认知损害老年患者记忆减退症状的1年随访[J].中国中药杂志.2003,28(10)：987-991
[17]成龙.中药金思维对A β所致AD大鼠模型脑血管和神经元损伤的保护机制研究.北京中医药大学博士研究生学位论文.2003
[18]李小黎.金思维提取物对A β致类AD模型神经元突触的保护作用及其机制研究.北京中医药大学博士研究生学位论文.2004
[19]徐意.金思维提取物对AD模型鼠脑内β淀粉样肽及神经可塑性的影响.北京中医 药大学博士研究生学位论文.2005
[20]张雷明.金思维提取物对AD模型小鼠脑内β-淀粉样肽生成与降解的调节作用.北京中医药大学博士研究生学位论文.2009
[21]温世荣,王德生,张景艳,等.复智散对淀粉样β蛋白25-35神经细胞毒性效应的影响及其机制[J].中国临床康复.2005,9(13)：248
[22]俭剑非,任常山,尹元琴.EGb761对阿尔茨海默病大鼠脑内ChAT活性及神经元凋亡的影响[J].中国实用内科杂志.2007,27(10):792
[23]钟振国,屈泽强,王乃平,等.三七总皂苷对阿尔茨海默病大鼠脑胆碱能神经的保护作用[J].中国临床康复.2006,10(19)：174
[24]王晓英,陈霁,张均田.人参皂苷Rg1对β 2淀粉样肽(25-35)侧脑室注射所致小鼠学习记忆障碍的改善作用及其机制[J].药学学报.2001,36(1):1-4
[25]刘卫刚,肖向建,李敏,等.石杉碱甲对体外培养大鼠脊髓片前角运动神经元损伤的保护作用[J].中国新药与临床杂志.2005,24(12)：933-937
[26]章海燕,唐希灿.石杉碱甲：具有治疗神经退行性疾病的前景药物[J].上海医药.2003,24(3)：112 120.
[27]曾育琦,陈晓春,黄春等.人参皂苷Rgl通过调节GSK23 (βPPP2A活性减轻皮层神经元Tau蛋白过度磷酸化.解剖学报.2007,38(6)：665-667
[28]谢玉华,陈晓春,张静等.人参皂苷可能通过CDK5途径减轻A β 25-35诱导的胎鼠海马神经元tau蛋白过度磷酸化[J].药学学报.2007,42：828-832
[29]宋锦秋,陈晓春,张静,等.人参皂苷Rbl通过JNK_p38 MAPK途径减轻A β 25-35诱导的胎鼠皮层神经元tau蛋白过度磷酸化[J].药学学报.2008,43:29-34
[30]李国栋,袁保梅,鄢文海等.人参皂苷Rbl对内源性A β所致小鼠神经细胞tau蛋白过磷酸化的干预作用.山东医药.2009,49(3)：26-27
[31]钟雷,谭洁,欧阳石等.知母皂苷B对大鼠海马注射A β 25-35致tau蛋白磷酸化的影响[J].南方医科大学学报.2006,26(8)：1106-1109
[32]Peng JH,Zhang CE,Wei W, Hong XP, Pan XP, Wang JZ. Dehydroevodiamine attenuates tau hyperphosphorylation and spatial memory deficit induced by activation of glycogen synthase kinase-3 in rats[J]. Neuropharmacology 2007;52:1521-1527
[33]顾明,周慧芳,薛冰,等.雷公藤单体T10对A β1-42所致PC1 2细胞调亡的抑制作用[J].生理学报.2004,56(1)：73
[34]吴蕾,陈云波,王奇,等.人参皂苷对A β 25235蛋白诱导的老年性痴呆体外模型NG10821 5神经元细胞凋亡的抑制作用[J].广州中医药大学学报.2007,24(2)：126
[35]李龙宣,赵斌,许志恩,等.熟地黄抑制阿尔茨海默病样大鼠海马神经元凋亡的作 用[J].中华神经医学杂志.2006,5(1)：10
[36]谢宁,宋琳,姚丽芬,等.地黄饮子对阿尔茨海默病模型鼠脑神经元细胞凋亡及超微结构的影响[J].中国临床康复.2005,9(37)：93
[37]王小艳,董军,陆大祥,等.中药复方SM I对拟老年痴呆小鼠学习记忆能力及海马BDNF表达的影响[J].中国病理生理杂志.2005,21(3)：524
[38]张兰,李林,李斌等.中药参乌胶囊对老年大鼠学习记忆及海马组织学的影响[J]中国康复理论与实践.2002,8(9)：516
[39]黄理钧,龚俊华,梁烨,等.益智健脑颗粒对AD模型大鼠学习记忆能力及海马神经元BDNF表达的影响[J].中国行为医学科学.2006,15(9):780
[40]丁向东,冯月英,张健新,等.升黄益智方对氯化铝所致痴呆模型小鼠行为学及脑组织神经递质的影响[J].中国老年学杂志.2004,24(12):1183
[41]康湘萍,金国琴,赵伟康,等.调心方有效部位TX0201对A β 25-35所致类“AD”大鼠氧化损伤及能量代谢的影响[J].中药药理与临床.2005,21(2):23
[42]杨戈,林水淼,赵伟康,等.达纳康对类老年痴呆大鼠脑组织胶质细胞原纤维酸性蛋白和IL21 β、IL26及APPmRNA表达的影响[J].北京中医药大学学报.2006,29(12)：816
[43]张桂娟,马民,马义.脑康冲剂治疗阿尔茨海默病的临床与实验研究[J].中国老年学杂志.2006,26:619
[44]周志昆,曾红兵.黄芪三仙汤对Alzheimer模型大鼠脑海马区免疫炎性反应的影响[J].中药药理与临床.2006,22(2)：48
[45]Bubber P, Haroutumian V, Fish G, et al. Mitochondrial abnormalities in Alzheimer brain:mechanistic implications[J]. Ann Neurol.2005; 57 (5):695
[46]赵丽波,张林,邬英全,等.A β 25-35致PC12细胞膜线粒体损伤及人参皂苷对其影响[J].中国实验诊断学.2005,9(1)：67-69
[47]姚柏春,袁华,黄翔,等.喂饲绞股蓝皂苷对Aβ1-40注射海马后大鼠脑内COX活性和线粒体超微结构变化的影响[J].中国老年学杂志.2005,25(10):1193
[48]王杉,蒋宁,周文霞等.黄连解毒汤对快速老化模型小鼠海马蛋白表达的影响[J].中国中药杂志.2007,32(21)：2289-2294
[49]徐建民.益智汤抗老年期痴呆的实验研究[J].中国中医药科技,2007,14(4):279.
[50]蔡大勇,陈金星,张伟.丹栀逍遥散干预D2半乳糖拟老年性痴呆大脑能量物质代谢的机制研究[J].航天医学与医学工程.2005,18(2):32
[51]沈映君.中药药理学[M].北京：人民卫生出版社,2000
[52]张均田.人参皂苷Rgl的促智作用机制对神经可塑性和神经发生的影响[J].药学学报.2005,40(5)：385-388
[53]中国医学科学院药物研究所.中草药现代研究(第二卷).北京：北京医科大学中 国协和医科大学联合出版社.1996.440,442,450,444
[54]黄芪、构杞子对衰老大鼠SOD,LPO及其某些激素的影响[J].中药药理与临床.1999,18(6)：20
[55]杨敏.黄芪对慢性低02高C02大鼠学习记忆能力的影响[J].中国热带医学.2008,8(1)：28-29
[56]尹艳艳,公惠玲,李维祖,等.黄芪总苷对血管性痴呆小鼠学习记忆功能的影响[J].安徽医药,2009,13(9)：1018-1020.
[57]李献平等.四大怀药延缓衰老作用的研究[J].中西医结合杂志.1991,11(8)：486
[58]郝志奇,等.山药水煎剂对实验性小鼠的降血糖作用[J].中国药科大学学报.1991,22(3)158
[59]吕圭源,李万里.白术抗衰老作用研究[J].现代应用药学.1996,13(5):26-29
[60]李怀荆,郭忠兴.白术水煎剂对老年小鼠抗衰老作用的影响[J].佳木斯医学学报.1996,19(1)：9
[61]明亮,等.白芍总苷对小鼠学习记忆行为的影响.安徽医科大学学报.1993,28(1):19
[62]刘一流,李续娥.何首乌蛋白质和葸醌苷对D-半乳糖衰老小鼠学习记忆及代谢产物的影响[J].广州中医药大学学报.2009,26(2)：160-163.
[63]刘孟渊,刘惠纯.益智中草药的研究概况[J].中国中西医结合杂志.2002,15(1):59
[64]王月芳,万海同.论肾虚痰凝血瘀是老年性痴呆的重要发病机制[J].中国中医基础学杂志.2001,5(8)：9
[65]聂晶,罗勇,龚其海,等.淫羊藿苷对三氯化铝诱导痴呆大鼠模型脑内胆碱能系统的影响[J].上海中医药杂志.2008,42(4)：69-72
[66]楚晋,李林,叶翠飞,等.淫羊藿黄酮对APP转基因小鼠学习记忆及β-amyloid生成的影响[J].中国科学技术大学学报.2008,38(4)：439-448
[67]唐洪梅,李锐,周莉玲.石菖蒲对中枢神经系统作用研究进展[J].广州中医药大学学报.2000(2)：21
[68]黄兆胜.中药对老年性痴呆中枢神经递质改变调节[J].时珍国医国药.1999,10(9)：699
[69]陈勤,高晨曦,葛礼浩.远志皂苷对脑定位注射Aβ1-40拟AD大鼠脑内神经形态病理学变化的影响[J].激光生物学报.2006,15(3)：294-298
[7 0]陈勤,曹炎贵,张传惠.远志皂苷对β-淀粉样肽和鹅膏氨酸引起胆碱能系统功能降低的影响[J].药学学报.2002,37(12)：913-917
[71]Kim H M, Lee E H, Na H J, et al. Effect of polygalatenuifolia root extract on the tumor necrosis factor-a secretion from mouse astrocytes [J].J Ethnop-harmacol.1998; 61:201-208
[72]穆俊霞,李新毅.中药远志对阿尔茨海默病大鼠模型学习记忆和胆碱酯酶活性的影响[J].世界中西医结合杂志.2007,2(1)：18-20
[73]He LN, He S B, Yang J. Protective effect of Tanshinones on primary cultured cortex neurons injury induced by ischemia. Chinese Pharmacological Bulletin.2001; 17(2):214-216
[74]索国玲,唐洪丽等.丹参对幼年大鼠癫痫持续状态学习记忆及海马ChAT、AChE活性的影响.东南大学学报.2007,26(4)：271-274
[75]张旭静,曹奕丰,冯春红.川芎、当归对大鼠血栓形成的影响[J].中国临床药学杂志.2002,11(1)：45
[76]王红,等.葛根及川芎对动物学习记忆的影响.中日友好医院学报.1995,9(4)：191
[77]马娜,朱东海.益智仁提取物对β淀粉样肽致小鼠学习记忆障碍的改善作用及机制分析[J].中国医药导刊.2009,11(7):1175-1176
[78]李克才.益智仁对水蚤寿命的影响[J].生物学杂志.1999,(4)：20.
[79]阳辛凤.利美莲益智与益智酒抗氧化活性的研究[J].华南热带农业大学学报.2001,(3)：20
[80]詹向红,李德新.中医药防治阿尔茨海默病实验研究述要[J].中医药学刊.2004,22(11)：2096
[81]颜乾麟,邢斌.阿尔茨海默病中医治疗目的和方法的拓展.中医杂志.2003,44(10)725
[1]Selkoe D J,The Pathophysiology of Alzheimer's disease. In:Scinto L. F. M., Daf fnerK. R. (Ed.):Early Diagnosis of Alzheimer's Disease. Totowa, New Jersey:Humana Press.2000; 83-104
[2]Lynch C., Mob ley W. Comprehensive Theory of Alzheimer's Disease:The Eeffect of Cholesterol on Membrane Receptor Trafficing. In:Khachaturian Z. S, Mesulam M. M. (Ed.). Alzheimer's Disease:A Compendium of Current Theories. The New York Academy of Sciences, New York.2000; 104-111
[3]Neuroinflammation Working Group. Inflammrtion and Alzheimer's disease. Neuroboil Aging.2000;21 (3):383-421
[4]Abstract from the 9th international conference on Alzheimer's Disease and related disorders. Neurobioiogy of Aging.2004;25(S2):S1-S654
[5]Simons M, Schwarzler F, Lut J E,et,al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer's Disease:A 26-week randomized, placebcontrolled,double-blind trail.Ann Neurol.2002;52 346-350
[6]沈渔邨,李永彤,李格等.Alzheimer性痴呆危险因素的病例对照研究.中华神经精神科杂志.1992,25:284-287
[7]Moreira PI,Zhu X, Lee HG.et al.The (un)blance between metabolic and oxidative abnormalities and cellular compensatory responses in Alzheimer' s Disease. Mechanisms of ageing and development.2006; 127:501-506
[8]马永兴,俞卓伟.北京：现代痴呆学.科学技术文献出版社,2008
[9]Tatebayashi Y, Haque N, Tung Y C, et al.Role of Tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport [J]. J Cell Sci.2004; 117:1653-1663.
[10]Lefebvre T, Ferreira S, Dupont-Wal lois L, et al. Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins-a role in nuclear localization [J].Biochim Biophys Acta.2003; 1619(2):167-176.
[11]Eun Jeoung Lee, Sung Hee Hyun, Jaesun Chun,et al. Regulation of Glycogen Synthase Kinase 3β Functions by Modification of the Small Ubiquitin-Like Modifier. Open Biochem J.2008; 2:67-76.
[12]Berrino F. Western diet and Alzheimer's disease. Epidemiol Prev.2002; 3(2):107-115
[13]Park CR. Cogniitive effects of insulin in the central nervours system. Neurosic Biobehav Rev.2001; 25:311-323
[14]Craft S, Dagogo-Jack SE, Wiethop BV, et al. Effects of hyperglycemia on memory and hormone levels in dementia of the Alzheimer type:a longitudinal study.Behave Neuroscience.1993:107:926-940
[15]盛树力.糖尿病脑病与老年性痴呆.中华内分泌代谢杂志.2001,17：58-59
[16]Webber KM,Raina AK,Marlatt MW, et al.The cell cycle in Alzheimer disease:unique target for neuropharmacology. Mechanisms of Ageing and development.2005; 126:1019-1025
[17]Holmes C, Boche D, Wilkinson D et al. Long-time effects of Abeta(42) in Alzheimer's disease:Follow-up of a randomised,placebo controlled phase Ⅰ trial [J]. Lancet.2008; 372(9634):216
[18]Gomez-Ramos A, Dominguez J, Zafra D, et al. Inhibition of GSK-3 Dependent Tau Phosphorylation by Metals.Curr Alzheimer Res,2006;3(2):123-127.
[19]Le Corre S,Klafki HW,Plesnila N,et al. An inhibitor of tau hyperphosphorylation prevent s severe motor impairment s in tau transgenic mice [J]. Proc Natl Acad Sci USA.2006;103 (25):9673-9678.
[20]Pickhardt M, Gazova Z, von Bergen M, et al. Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired elical filament s in vitro and in cells [J]. JBiol Chem.2005; 280 (5):3628-3635.
[21]Yuzwa, S A; Macauley,M S; Heinonen, J E, et al. A potent mechanism inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo[J].Nat-Chem-Biol.2008; 4(8):483-490
[22]徐剑文,俞昌喜.阿尔茨海默病实验性动物模型的研究进展.国外医学·老年医学分册.2008,29(3)：97-103
[23]徐剑文.PTEN在铝毒性实验性阿尔茨海默病小鼠模型发生发展中的变化.福建医科大学硕士论文,2008
[24]F. Hefti, A. Dravid,J. Hartikka. Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase activity in adult rats with partial septo-hippocampal. Brain Research.1984; 293(2):305-311
[25]Ahmed MM, Hoshino H, Chikuma T, Yamada M, Kato T.Effect of memantine on the levels of glial cells, neuropeptides, and peptide-degrading enzymes in rat brain regions of ibotenic acid-treated alzheimer's disease model. Neuroscience.2004; 126(3):639-649
[26]Moran PM, Higgins LS, Cordell B, Moser PC. Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein. Proc Natl Acad Sci U S A.1995; 92 (12): 5341-5345
[27]Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature.1995; 373 (6514):523-527
[28]Miao J, Xu F, Davis J, Otte-Holler I, Verbeek MM, Van Nostrand WE. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol. 2005; 167 (2):505-515
[29]Richardson, RL, Kim, Eun-Mee, Shephard, RA, Gardiner, T, Cleary, J, O'Hare, E. Behavioural and histopathological analyses of ibuprofen treatment on the effect of aggregated A beta ((1-42)) injections in the rat. Brain Research.2002; 954 (1):1-10
[30]Nabeshima T. Trial to produce animal model of Alzheimer's disease by continuous infusion of beta-amyloid protein into the rat cerebral ventricle. Nihon Shinkei Seishin Yakurigaku Zasshi.1995; 15(5):411-418
[31]Cui X, Zuo P, Zhang Q, Li X, Hu Y, Long J, Packer L, Liu J. Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice:protective effects of R-alpha-lipoic acid. J Neurosci Res.2006; 84(3):647-654-
[32]Kuo H, Ingram DK, Walker LC, Tian M, Hengemihle JM, Jucker M. Similarities in the age-related hippocampal deposition of periodic acid-schiff-positive granules in the senescence-accelerated mouse P8 and C57BL/6 mouse strains. Neuroscience.1996;74 (3):733-740
[33]Poon HF, Farr SA, Thongboonkerd V, Lynn BC, Banks WA, Morley JE, Klein JB, Butterfield DA. Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid:implications for aging and age-related neurodegenerative disorders. Neurochem Int.2005; 46 (2):159-168.
[34]Jong-Hwan Lee, Hea-Nam Hong, Jin-Ok Im, Hong-Seob Byun and Donghou Kim. The formation of PHF-1 and SMI-31 positive dystrophic neurites in rat hippocampus following acute injection of okadaic acid. Neuroscience Letters.2000; 282 (1-2):49-52
[35]Gotz J, Probst A, Spillantini MG, Schafer T, Jakes R, Burki K, Goedert M. Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J. 1995; 14(7):1304-1313.
[36]Jada Lewis, Eileen McGowan, Julia Rockwood, Heather Melrose, Parimala Nacharaju, Marjon Van Slegtenhorst, Katrina Gwinn-Hardy, M. P Murphy, Matt Baker, Xin Yu, Karen Duff, John Hardy, Anthony Corral, Wen-Lang Lin, Shu-Hui Yen, Dennis W. Dickson, Peter Davies, Mike Hutton. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genetics.2000;25:402-405
[37]Blokland A, Jolles J. Spatial learning deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin. Pharmacol Biochem Behav.1993; 44 (2):491-494
[38]Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozo-tocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis.2006; 9(1):13-33
[39]Bennett MC, Rose GM. Chronic sodium azide treatment impairs learning of the Morris water maze task. Behav Neural Biol.1992;58 (1):72-75
[40]Florence AL, Gauthier A, Ponsar C, Van den Bosch de Aguilar P, Crichton RR. An experimental animal model of aluminium overload. Neurodegeneration. 1994; 3(4):315-323.
[41]张章,俞昌喜.褪黑素对侧脑室注射氯化铝致小鼠学习记忆障碍的改善作用及其机制.药学学报.2002,37:682-686
[42]陈贵海,尹世杰,周江宁.突触改变与Alzheimer病发病的关系.中华神经科杂志.2003,36:228-230
[43]BraakH, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl).1991; 82:239-259
[44]KleinWL, Krafft GA, Finch CE. Target ing sma11 Aβ oligomers:the solution to an Alzheimer's disease conundrum? Trends Neurosci.2001; 24:219-224
[45]Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature.200; 416:535-539
[46]Lee HG, Castellani RJ, Zhu XW, et al. Amyloid-β in Alzheimer's disease: the horse or the cart? Pathogenic or protective? Int J Exp Path.2005; 86: 133-138
[47]Baum LW. Sex, hormones, and Alzheimer's disease. J Gerontol A Biol Sci Med Sci.2005; 60:736-743
[48]Khachaturian Z. S. Epilogue:Toward a Comprehensive Theory of Alzheimer' s Disease-Challenge,Caweats,and Parameters. In:Khachaturian Z. S., Mesulam M.M. (Ed.). Alzheimer's Disease:A Compendium of Current Theorise. The New York Academy of Sciences, New York.2000;184-194
[49]蔡琰.老年性痴呆研究进展.国内外医学科学进展.卫生部科技教育司上海市医学科学技术情报研究所.2001,96-99
[50]王奕,金国琴.阿尔茨海默病的“有害网络”.中国老年学杂志.2003,23(2)：128-131
[51]Lefebvre T, Ferreira S, Dupont-Wallois L, et al. Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins-a role in nuclear localization[J]. Biochim Biophys Acta.2003; 1619 (2):167-176.
[52]Liu F, Iqbal K, Grundke-Iqbal I, et al. O-GlcNAcylation regulates phosphorylation of tau:a mechanism involved in alzheimer's disease [J] Proc Natl Acad Sci USA.2004;101:10804-10809.
[53]Dias,W B; Hart,G W.O-GlcNAc modification in diabetes and Alzheimer's disease[J]. Mol-Biosyst.2007;3(11):766-72
[54]Yuzwa, S A;Macauley,M S;Heinonen, J E, et al.A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo[J]. Nat-Chem-Biol.2008; 4(8):483-90.
[55]Yanqiu Deng, Bin Li, Ying Liu, Khalid Iqbal,Inge Grundke-Iqbal, and Cheng-Xin Gong. Dysregulation of Insul in Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain-Implication for Alzheimer's Disease. The American Journal of Pathology.2009; 175(5):6-7
[56]Lee T F, Shiao YJ, Chen C F, et al. Effect of ginseng saponins on beta2amyloid2suppressed acetylcholine release fromrat hippocampal slices[J]. Planta Med.2001; 67(7):634-663.
[57]张均田,刘云,屈志炜,等.人参皂甙Rb1和Rg1对小鼠中枢神经递质和脑内蛋白质合成的影响[J].药学学报,1988,23(1)：12-16.
[58]Sal in K N,McEwen B S, Chao H M, et al. Ginsenoside Rbl regulates ChAT, NGF and trKA mRNA expression in the rat brain[J]. Brain Res Mol Brain Res.1997;47 (122):177-182.
[59]张静,黄天文,陈晓春,宋锦秋,曾育琦.人参皂苷Rg1通过CDK5途径减轻Aβ25235诱导的神经元tau蛋白磷酸化.福建医科大学学报.2008,42(1)：9-10.
[60]李国栋,袁保梅,鄢文海,邢莹.人参皂苷Rb1对内源性Aβ所致小鼠神经细胞Tau蛋白过磷酸化的干预作用.山东医药.2009,49(3)：26-27.
1.ICV-STZ大鼠存在明显的学习记忆障碍及海马神经元超微结构的破坏。
2.复方银思维有明显的改善ICV-STZ拟SAD大鼠空间学习记忆能力的作用。
3.复方银思维改善SAD大鼠学习记忆能力的超微形态学基础可能与保护海马神经元线粒体及轴突内微管结构有关。
[1]Sharma M, Gupta YK.Intracerebroventricular injection of streptozoto-cin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci.2001;68(9):1021-1029
[2]George Paxinos Charles Waston著,诸葛启钏译.The Rat Brain in stereotaxic coordinates (大鼠脑立体定向图谱)[M].北京：人民卫生出版社,2005,第3版
[3]李爱萍,赵慧,李韶,等.不同鼠种在Morris水迷宫学习记忆行为中的种属差异.中国行为医学科学.2005,14(1)：29-31
[4]沈政,林庶芝编著.生理心理学(第二版).北京：北京大学出版社,2007,84-115
[5]ArakiT, SasakiY, Milbrandt J. Increased nuclear NAD+ biosynthesis and SIRT1 activation prevent axonal degeneration [J]. Science,2004; 305:1010-1013
[6]Hung A. J., Stanbury M. G., Shanabrough M, et al. Estrogen, synaptic Plasticity and hypothalamic reproductive aging. ExperimentalGerontology.2003; 38: 53-59
[7]Sergeant N, David J, Champain D, et al. Progressive decrease of amyloid p recursor p rotein carboxy terminal fragments (APP-CTFs), associated with tau pathology stages, in Alzheimer's disease[J]. J Neurochem,2002; 81 (4):663.
[8]Hanger DP, Brion JP. Tau in Alzheimer's disease and Down's syndrome is insoluble and abnormally phosphorylated [J].Biochem J,1991; 275:99-140.
[9]龚成新,王建枝.tau蛋白在老年性痴呆症神经原纤维退行性变中的作用.医学分子生物学杂志.2006,3(3)：163-169
[10]Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Post-translational modifications of tau protein in Alzheimer's disease. J Neural Transm.2005; 112(6): 813-838
[11]王蓉,邵志敏,盛树力.3型糖尿病-散发性老年性痴呆研究的新观点.中华老年多器官疾病杂志.2007,6(1)：17-18
[12]Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3 diabetes?J Alzheimers Dis.2005; 7(1):63-80
[13]Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis.2006; 9 (1):13-33.
[14]RM O'Br ien, RS Streeper, JE Ayala, et al. Insul in-regulated gene expression. Biochem Soc Trans.2001; 29(Pt4):552-558
[15]C. R. Park.Cognitive effects of insulin in the central nervous system Purchase. Neuroscience & Biobehavioral Reviews.2001; 25(4):311-323
[16]Gasparini L, Netzer WJ, Greengard P, Xu H. Does insulin dysfunction play a role in Alzheimer's disease? Trends Pharmacol Sci.2002; 23(6):288-293
[17]盛树力.糖尿病脑病与老年性痴呆.中华内分泌代谢杂志.2001,17:58-59
[18]Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S.Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone:a preliminary study. Am J Geriatr Psychiatry.2005; 13(11):950-958
[19]Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease:follow-up of a randomised, placebo-controlled phase Ⅰ trial. Lancet.2008; 372(9634):216-223.
[20]Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci.2001; 68(9):1021-1029
[21]Shoham S, Bejar C, Kovalev E, Weinstock M. Intracerebroventricular injection of streptozotocin causes neurotoxicity to myelin that contributes to spatial memory deficits in rats. Exp Neurol.2003; 184 (2) :1043-1052
[22]Weinstock M, Shoham S.Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity. J Neural Transm.2004; 111 (3):347-366
[23]Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis.2006;9(1):13-33
[24]Tiwari,-V; Kuhad,-A; Bishnoi,-M; Chopra,-K.Chronic treatment with tocotrienol, an isoform of vitamin E, prevents intracerebroventricular streptozotocin-induced cognitive impairment and oxidative-Nitrosative stress in rats. Pharmacol-Biochem-Behav.2009;93 (2):183-189
[25]Hoyer,-S; Lannert,-H. Long-term effects of corticosterone on behavior, oxidative and energy metabolism of parietotemporal cerebral cortex and hippocampus of rats:comparison to intracerebroventricular streptozotocin. J-Neural-Transm.2008;115 (9):1241-1249
[26]Tauheed Ishrat, Kehkashan Parveen, Mohd. Moshahid Khan, Gulrana Khuwaja, M. Badruzza-man Khan, Seema Yousuf, Ajmal Ahmad, Pallavi Shrivastav and Fakhrul Islam.Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer's type. Brain Research.2009; 1281:117-127
[27]Blokland A, Jolles J. Spatial learning deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin. Pharmacol Biochem Behav.1993;44 (2):491-494
[28]Roman Duelli, Helmut Schrock, Wolfgang Kuschinsky, Siegfried Hoyer. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. International Journal of Developmental Neuroscience.1994; 12 (8):737-743
[29]Lannert H, Hoyer S.Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998; 112(5):1199-1208
[30]Hoyer S, Lee SK, Loffler T, Schliebs R. Inhibition of the neuronal insulin receptor. An in vivo model for sporadic Alzheimer disease? Ann N Y Acad Sci.2000; 920:256-258
[31]Hoyer S. The brain insulin signal transduction system and sporadic (typeⅡ) Alzheimer disease:an update. J Neural Transm.2002;109(3):341-360
[32]G J Biessels,F-E De Leeuw, J Lindeboom,et al. Increased cortical atrophy in patients with Alzheimer disease and type2 diabetes mellitus. J Neurol Neurosurg Psychiatry.2006; 77:304-307
[33]WZ Chu and CY Qian. Expressions of Abeta1-40, Abeta1-42, tau202, tau396 and tau404 after intracerebroventricular injection of streptozotocin in rats.Di Yi Jun Yi Da Xue Xue Bao.2005; 25 (2):168-170
[34]Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis.2006;9 (1):13-33
[35]Sonkusare S, Srinivasan K, Kaul C, Ramarao P.Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats. Life Sci.2005; 77(1):1-14
[36]Hoyer S.Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol.2004; 490 (1-3):115-125
[37]Duelli R, Schrock H, Kuschinsky W, Hoyer S. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci.1994;12(8):737-743
[38]Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998; 112(5):1199-1208
[49]Shoham S, Bejar C, Kovalev E, Schorer-Apelbaum D, Weinstock M. Ladostigil prevents gliosis, oxidative-nitrative stress and memory deficits induced by intracerebroventricular injection of streptozot-ocin in rats. Neuropharmacology.2007;52 (3):836-843
[40]Tuppo EE, Arias HR. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol.2005; 37(2):289-305
[41]Finch CE. Neurons, glia, and plasticity in normal brain aging. Neurobiol Aging.2003; 24 Suppl 1:S123-127, discussion S131
[42]Prickaerts J, Fahrig T, Blokland A. Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i. c. v. injection of streptozotocin:a correlation analysis. Behav Brain Res. 1999; 102(1-2):73-88
[43]Rodrigues L, Biasibetti R, Swarowsky A et al. Hippocampal alterations in rats submitted to streptozotocin-induced dementia model are prevented by aminoguanidine. J Alzheimers Dis.2009; 17(1):193-202
[44]Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? J Alzheimers Dis.2005; 7(1):63-80.
[45]Hellweg R, Nitsch R, Hock C, Jaksch M, Hoyer S. Nerve growth factor and choline acetyltransferase activity levels in the rat brain following experimental impairment of cerebral glucose and energy metabolism. J Neurosci Res.1992; 31 (3):479-486
[46]符鹏程,杨期东等.脑室注射链脉佐菌素对大鼠空间学习记忆能力、海马CAI区神经元的数量和海马突触素表达的影响.神经解剖学杂志.2009,25(3)：249-254
[47]符鹏程.吡格列酮对AO大鼠记忆障碍的作用及其机制的研究.中南大学湘雅医院博士研究生论文.2009
[48]Moser MB, Moser EI, Forrest E, Andersen P, Morris RG. Spatial learning with a minislab in the dorsal hippocampus. Proc Natl Acad Sci U S A. 1995;92 (21):9697-9701
[49]Kucukatay V, Balkan S, Yara N, Yargicolu P, Aar A. The effect of pergolide on cognitive performance of young and middle-aged rats. Int J Neurosci.2002; 112(9):1027-1036
[50]张均田.人参皂苷Rg1的促智作用机制对神经可塑性和神经发生的影响[J].药学学报.2005,40(5)：385-388
1.ICV-STZ大鼠大脑皮层与脑能量代谢及线粒体功能相关的SDH、COX、 Na+-K+-ATPase酶活性低下,且大脑皮层ChAT活性低下,而AchE活性增高,存在明显的脑能量代谢障碍及胆碱能系统紊乱。
2.复方银思维能显著提高ICV-STZ拟SAD大鼠皮层SDH、COX、Na+-K-ATPase的活性,从而改善脑组织能量代谢及线粒体功能。
3.复方银思维能够提高ICV-STZ拟SAD大鼠大脑皮层ChAT活性,同时使得AchE活性下降,从而调节胆碱能神经递质的合成与代谢平衡。
[1]Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci.2001; 68 (9):1021-1029
[2]George Paxinos Charles Waston著,诸葛启钏译.The Rat Brain in stereotaxic coordinates(大鼠脑立体定向图谱)[M].北京：人民卫生出版社,2005,第3版
[3]王琴,黄慧玲,刘锐等.亚低温对急性颅脑创伤大鼠线粒体呼吸链酶活性的影响.天津医药.2000,36(7)：524-526
[4]Blass J P, Gibson G E, Hoyer S. The role of the metabolic lesion in Alzheimer' s Disease. J Alzheimer's Dis.2002; 4:225-232
[5]Blass J P. The Mitochondrial spiral An adequate cause of dementia in the Alzheimer's syndrome. In:Khachaturian Z. S.,Mesulam M. M. (Ed.), Alzheimer' s Disease:A Compendium of Current Theories. The New York Academy of Sciences, New York, ANN N Y ACAD SCI.2000;924:170-183
[6]Papa S. Mitochondrial oxidative phosphorylation changes in the life span: Molecular aspects and physiological implications [J]. Biochem Biophys Acta, 1996; 1276 (2):87-105.
[7]S Hoyer. Memory function and brain glucose metabolism. Pharmacopsychiatry. 2003; 36 (Suppll):S62-S67
[8]Torlinska T, Grochowalska A. Age-related changes of NA+-K+-ATPase, Ca+2-ATPase and Mg+2-ATPase activities in rat brain synaptosomes. J Physiol Pharmacol,2004;55 (2):457
[9]Gil-Bea F J, Garcia-AllozaM, DominguezJ, et al. Evaluation of cholinergic markers in Alzheimer's disease and in a modelof cholinergic deficit [J]. Neurosci Lett,2005;375:37
[10]Duelli R, Schrock H, Kuschinsky W, Hoyer S. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci.1994; 12(8):737-743
[11]Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998; 112(5):1199-1208
[12]Tauheed Ishrat, M. Badruzzaman Khan, Md. Nasrul Hoda, Seema Yousuf, Muzamil Ahmad, Mubeen A. Ansari, Abdullah S. Ahmad and Fakhrul Islam. Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats. Behavioural brain research.2006; 171(1):9-16.
[13]Tauheed Ishrat, Kehkashan Parveen, Mohd. Moshahid Khan, Gulrana Khuwaja, M. Badruzzaman Khan, Seema Yousuf, Ajmal Ahmad, Pallavi Shrivastav and Fakhrul Islam. Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer's type. Brain Res.2009; 1281:117-127.
[14]Swapn.il Sonkusare, Krishnamoorthy Srinivasan, Chamanlal Kaul and Poduri Ramarao. Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats. Life Sci. 2005; 77(1):1-14.
[15]Liu M, Zhang J.Effects of ginsenoside Rbl and Rgl on synaptosomal free calcium level, ATPase and calmodul in in rat hippocampus. Chin Med J (Engl). 1995; 108(7):544-547. 存在tau的异常O-GlcNAc糖基化修饰。
2.复方银思维能明显提高ICV-STZ拟SAD大鼠海马组织tau蛋白的O-GlcNAc糖基化修饰水平。
3.复方银思维能显著提高SAD模型大鼠海马OGT的表达,降低O-GlcNAcase的表达,从而对tau蛋白O-GlcNAc糖基化修饰产生正向作用。
[1]Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci.2001; 68(9):1021-1029
[2]George Paxinos Charles Waston著,诸葛启钏译.The Rat Brain in stereotaxic coordinates (大鼠脑立体定向图谱)[M].北京：人民卫生出版社,2005,第3版
[3]龚成新,王建枝.tau蛋白在老年性痴呆症神经原纤维退行性变中的作用.医学分子生物学杂志,2006;3(3)：163-169
[4]Tatebayashi Y, Haque N, Tung Y C, et al.Role of Tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport [J]. J Cell Sci,2004; 117:1653-1663.
[5]Ebneth A, Godemann R, Stamer K, et al. Over expression of Tau protein inhibits kinesin-dependent trafficking of vesicles,mitochondria and endop lasmic reticulum:implications for Alzheimer's disease[J]. J Cell Biol,1998; 143: 777-7941
[6]Hua Q, He R Q, Haque N, et al. Microtubule associated p rotein tau binds to double-stranded but not single-stranded DNA[J]. CellMol Life Sci,2003; 60:413-421
[7]Bhaskar K, Yen S H, Lee G. Disease related modifications in tau affect the interaction between fyn and tau [J]. J Biol Chem,2005; 280 (42):35119-35125
[8]Iqbal K, Grundke-Iqbal I.Discoveries of tau,abnormallly Hyperphosp-horylated tau and others of neurofibrillary degeneration:a personal historical perspective.J Alzheimer's Dis.2006; 9(3 Suppl):219-242
[9]Utton MA, Noble WJ, Hill JE, et al. Molecular motors implicated in the axonal transport of tau and alpha-synuclein. J Cell Sci.2005; 118:4645-4654
[10]Kepke E, Tung Y C, Sha Ikh S, et al. Microbutule associated protein tau: abnormal phosphorylation of a non-paired helical filament pool in alzheimer disease [J].J Biol Chem,1993;268:24374-24384
[11]第五永长,田金洲.Tau蛋白磷酸化及O-GlcNAc糖基化修饰与阿尔茨海默病.中风与 神经疾病杂志.2010,27(3)：111
[12]C. R. Torres and G. W. Hart, J. Biol.Chem.,1984; 259,3308-3317
[13]N. E. Zachara and G. W. Hart, Biochim. Biophys. Acta,2006; 1761,599-617.
[14]D. C. Love and J. A. Hanover, Sci.STKE,2005; 2005, re13.
[15]K. Vosseller, J. C. Trinidad, R. J. Chalkley, C. G. Specht, A. Thalhammer, A. J. Lynn, J.O. Snedecor, S. Guan, K. F. Medzihradszky, D. A. Maltby, R. Schoepfer and A. L. Burlingame, Mol.Cell. Proteomics,2006; 5,923-934.
[16]N. Khidekel, S. B. Ficarro, E. C. Peters and L. C. Hsieh-Wilson, Proc. Natl. Acad. Sci. U. S. A.,2004; 101,13132-13137.
[17]A. Nandi, R. Sprung, D. K. Barma, Y. Zhao, S. C. Kim, J. R. Falck and Y. Zhao, Anal. Chem.,2006; 78,452-458.
[18]Z. Wang, A. Pandey and G. W. Hart, Mol. Cel 1. Proteomics,2007; 6,1365-1379.
[19]Dias,W B; Hart,G W.O-GlcNAc modification in diabetes and Alzheimer's disease[J]. Mol-Biosyst.2007; 3(11):766-772
[20]Hart G W. Dynamic 0-linked glycosylation of nuclear and cytoskeletal proteins [J]. Annu Biochem,1997; 66(1):315-335
[21]Hoyer S. Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease:therapeutic implications [J]. Adv Exp Med Biol,2004; 541:135-152
[22]Gong C X, Liu F, Grundke-Iqbal I, et al. Impaired brain glucose metabolism leads to alzheimer neurofibrillary degeneration through a decrease in tau o-GlcNAcylation[J].J Azheimer's Dis,2006; 9 (1):1-12.
[23]Hart G W, Greis K D, Dong L Y, et al.0-linked N-acetylglucosamine:the "yin-yang" of Ser/Thr phosphorylation Nuclear and cytoplasmic glycosy-lation[J]. Adv Exp Med Biol,1995; 376:115-23
[24]Liu F, Iqbal K, Grundke-Iqbal I, et al. O-GlcNAcylation regulates phosphorylat ion of tau:a mechanism involved in alzheimer's disease [J] Proc Natl Acad Sci USA,2004; 101:10804-10809.
[25]Planel E,Miyasaka T,Launey T,et al. Alterations in glucose metabolism induce hypothermia leading to tauhyperphosphorylation through different-ial inhibition of kinase and phosphatase activities:implications for Alzheimer's disease[J]. J Neurosci,2004; 24 (10):2401-2411
[26]Quinn CM, kagedal K, Terman A, et al. Induction of fibroblast apol ipoprotein E expression during apoptosis, starvation-induced growth arrest and mitosis[J]. Biochem J,2004; 37 (3):753-761
[27]Yanqiu Deng, Bin Li, Ying Liu, Khalid Iqbal, Inge Grundke-Iqbal, and Cheng-Xin Gong. Dysregulation of Insulin Signaling, Glucose Transporters, 0-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain-Implication for Alzheimer's Disease. The American Journal of Pathology.2009; 175(5):6-7
[28]Yuzwa, S A; Macauley, M S; Heinonen, J E, et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo[J].Nat-Chem-Biol.2008; 4(8):483-90
[29]Tallent,M K; Varghis,N; Skorobogatko, Y, et al. In Vivo Modulation of 0-GlcNAc Levels Regulates Hippocampal Synaptic Plasticity through Interplay with Phosphorylation[J]. J-Biol-Chem.2009; 284(1):174-81
[30]Xiaoyong Yang, Pat P. Ongusaha, Philip D. Miles, Joyce C. Havstad, Fengxue Zhang, W. Venus So, Jeffrey E. Kudlow, Robert H. Michell, Jerrold M. Olefsky, Seth J. Field & Ronald M. Evans. Phosphoinosit ide signal ling links O-GlcNAc transferase to insulin resistance. Nature.2008; 451:964-969
[31]宋丽娜,王京兰,钱小红,蔡耘.O-GlcNAc修饰蛋白质的生理功能和研究方法.生命的化学.2007,27(1)：14-16
[32]Khidekel N et al. Proc Natl Acad Sci USA,2004;101 (36):13132-13137
[33]Comer FI et al. Anal Biochem,2001; 293 (2):169-177
[34]Nandi A et al. Anal Chem,2006; 78(2):452-458
[35]Fei Liu, Jianhua Shi, Hitoshi Tanimukai, Jinhua Gu, Jianlan Gu, Inge Grundke-Iqbal, Khalid Iqbal and Cheng-Xin Gong. Reduced O-GlcNAcyla-tion links lower brainglucose metabolism and tau pathology in Alzheimer' s disease. Brain.2009; 132(7):1820 1832.
1. ICV-STZ大鼠海马组织tau蛋白重要位点Thr 231和Ser422的磷酸化P-Thr 231、P-Ser422表达增多,与实验三中脑组织tau的O-GlcNAc糖基化修饰水平呈反向关联,模型大鼠海马组织存在tau蛋白的异常磷酸化。
2.复方银思维能显著减少ICV-STZ拟SAD模型大鼠海马组织P-Thr 231、P-Ser422的表达,从而抑制tau蛋白在重要位点的异常过度磷酸化,防止tau毒性和进一步的纤维状结构形成。
[1]Gong CX, Liu F, Grundke-Iqbal I, Iqbal K.Post-translational modifications of tau protein in Alzheimer's disease. J Neural Transm.2005; 112 (6):813-838
[2]龚成新,王建枝.tau蛋白在老年性痴呆症神经原纤维退行性变中的作用.医学分子生物学杂志.2006；3(3)：163-169
[3]Cheng Xin Gong, Fei Liu, Inge Grundke-Iqbal, et al. Dysregulation of Protein Phosphorylation/Dephosphorylation in Alzheimer's Disease:A Therapeutic Target [J]. J Biomed Biotechnol.2006; 2006(3):31825
[4]Patrice Delobel, Isabelle Lavenir, Graham Fraser,et al.Analysis of Tau Phosphorylation and Truncation in a Mouse Model of Human Tauopathy Analysis of Mouse Tauopathy[J]. Am J Pathol. 2008;172 (1):123-131
[5]Liu F, Grundke-Iqbal I, Iqbal K, Gong CX.Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci.2005; 22 (8):1942-1950
[6]Tanaka T, Zhong J, Iqbal K, et al.The regulation of phosphorylation of tau in sy5y neuroblastoma cells:the role of p rotein phosphatases [J]. FEBS Lett.1998; 426(2):248-254.
[7]Bennecib M, Gong CX, Grundke-Iqbal I, Iqbal K.Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356. FEBS Lett.2001; 490 (1-2):15-22
[8]Pei J J, Gong C X, Anw, et al. Okadaic-acid-induced inhibition of p rotein phosphatase2a produces activation of mitogen-activated protein kinases erk1/2, mek1/2, and p70 s6, similar to that in alzheimer's disease[J]. Am J Pathol.2003; 163:845-858.
[9]Liu F, Iqbal K, Grundke-Iqbal I, et al.O-GlcNAcylation regulates phosphorylation of tau:a mechanism involved in alzheimer's disease [J]. Proc Natl Acad Sci USA.2004;101:10804-10809.
[10]Robertson L A, Moya KL, Breen K C. The potential role of tau p rotein o-glycosylation in alzheimer's disease [J].J Alzheimer's Dis.2004; 6 (5):489-495.
[11]Gong CX, Liu F, Grundke-Iqbal I, et al. Impaired brain glucose metabolism leads to alzheimer neurofibrillary degeneration through a decrease in tau o-GlcNAcylation[J]. J Azheimer's Dis.2006; 9 (1):1-12.
[12]Yuzwa,S A; Macauley, M S; Heinonen, J E, et al. A potent mechanism-inspired 0-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo[J]. Nat-Chem-Biol.2008; 4(8):483-90
[13]Fei Liu, Jianhua Shi, Hitoshi Tanimukai, Jinhua Gu, Jianlan Gu, Inge Grundke-Iqbal, Khalid Iqbal and Cheng-Xin Gong. Reduced 0-GlcNAcyla-tion links lower brainglucose metabolism and tau pathology in Alzheimer' s disease. Brain.2009; 132(7):1820 1832.
[14]Harada A, Oguchi K, Okabe S, et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein [J].Nature.1994; 369: 488-491
[15]Alonso A, Del C, Grundke-Iqbal I.Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules[J] Nature Med.1996; 2:783-787
[16]Alonso A, Del C, Grundke-Iqbal I, et al. Abnormal phosphorylation of tau and the mechanism of alzheimer neurof ibrillary degeneration:sequestration of microtubule-associated proteinsl and 2 and the disassembly of micro-tubules by the abnormal Tau[J]. Proc Natl Acad Sci USA.1997;94:298-303
[17]Hern a ndez F, Borrell J, Guaza C, Avila J, Lucas JJ. Spatial learning deficit in transgenic mice that conditionally over-express gsk-3beta in the brain but do not form tau filaments [J]. J Neurochem.2002; 83 (6): 1529-153
[18]Lee VM, Kenyon TK, Trojanowski JQ. Transgenic animalmodels of tauopathies [J].Biochim Biophys Acta.2005; 1739 (223):251-259
[19]Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Post-translational Modifications of tau protein in Alzheimer's disease. J Neural Transm.2005; 112 (6): 813-838
[20]Sengupta A, Kabat J, Novakm, et al. Maximal inhibition of tau binding tomicrotubules requires the phosphorylation of tau at both thr 231 and Ser 262 [J]. Neurobiol Ageing.1998; (19S):S124-524.
[21]Schneider A, B iernat J, Von Bergenm, et al. Phosphorylation that detaches tau p rotein from microtubules (ser262, ser214) also p rotects it against aggregation into alzheimer paired helical filaments[J]. Biochemistry. 1999; 38:3549-3558.
[22]Alonso A, Del C, Mederl Yova A, et al. Promotion of hyperphosphorylation by frontotemporal dementia taumutations[J]. J Biol Chem.2004; 279:34878-34881.
[23]Abraha A, Ghoshal N, Gamblin TC, Cryns V, Berry RW, Kuret J, Binder LI. C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease.J Cell Sci.2000; 113 (Pt21):3737-3745
[24]Haase C, Stieler J, Arend T T, et al. Pseudophosphorylation of tau p rotein alters its ability for self-aggregation[J]. J Neurochem.2004; 88:1509-1520.
[25]Ferrar IA, Hoerndl I F, Baech I T, et al. Beta-amyloid induces paired hel ical f ilament-like tau f ilaments in tissue culture [J]. J Biol Chem.2003; 278:40162-40168.
[26]严冬梅,李洪.磷酸化蛋白质检测技术研究进展.泸州医学院学报.2006,29(5)：460-461
[27]Goodman T, Schulenberg B, Steinberg TH, et al. Detection of phosphoproteins on electroblot membrarles using a small-molecule organic fluorophore [J]. Electrophoresis.2004; 25(15):2533
[28]Yanqiu Deng, Bin Li, Ying Liu, Khalid Iqbal,Inge Grundke-Iqbal, and Cheng-Xin Gong. Dysregulation of Insulin Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain-Implication for Alzheimer's Disease. The American Journal of Pathology.2009; 175(5):6-7
[29]Buerger K, Teipel S J, Zinkowski R, et al.CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MMI subjects [J]. Neurology.2002; 59 (4); 627-629.
[1]Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin like growth factor expression and signaling mechanisms in Alzheimer's disease is this type 3 diabetes? [J] J Alzheimer's Dis.2005; 7:63-80.
[2]Lester-Coll N, Rivera EJ, Soscia SJ, et al. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease[J]. J Alzheimers Dis.2006; 1:13-33
[3]Basu R, Breda E, Oberg AL, et al. Mechanisms of the age associated deterioration in glucose tolerance:contribution of alterations in insulin secretion, action,and clearance [J]. Diabetes.2003;52:1738-1745
[4]Basu R, Man CD, Campioni M, et al. Effects of age and sex on postprandial glucose metabolism:differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction[J]. Diabetes.2006; 55: 2001-2014
[5]赵路清,王鲁宁.胰岛素及胰岛素-胰岛素受体信号通路异常与阿尔茨海默病研究进展[J].中华老年医学杂志.2007,26(2)：152
[6]Watson GS, Peskind ER, Asthana S, et al. Insulin increases CSF Ab42 levels in normal older adults[J]. Neurology.2003; 60:1899-1903
[7]Zhao LX, Bruce T, Takashi M, et al. Insul in-degrading enzyme as a downstream target of insulin receptor signaling cascade; implication for Alzheimer's disease intervention[J].J Neurosci.2004; 24:11120-11126
[8]Suzanne Craft. Insulin Resistance and Alzheimer's Disease Pathogenesis: Potential Mechanisms and Implications for Treatment[J]. Current Alzheimer Research.2007; 4,147-152
[9]Skeberdis VA, Lan J, Zhang X, et al. Insulin promotes rapid delivery of N-methyl-D-asparate receptors to the cell surpace by exocytosi [J].Proc Natl Acad Sci USA.1998; 3561-3566
[10]Byrne JH. Learning and memery:basic mechanisms. In:Squire LR, Bloom FE, McConnell SK, etal. eds.Fundamental neuroscience.San Diego CA:Academic Press.2003; 1276-1298.
[11]Schubert M, Brazil DP, Burks DJ, et al. Insulin receptor substrate22 deficiency impairs brain growth and promotes tau phosphorylation[J]. J Neurosci.2003; 23:7084-7092
[12]Gasparini L, Netzer WJ, Greengard P, et al. Does insulin dysfunction play a role in Alzheimer's disease? [J]. Trends Pharmacol Sci.2002; 23:288-293
[13]Castillo DV, Figueroa-Guzman Y, Escobar ML. Brain-derive neurotrophic factor enhance conditioned taste aversion retention [J].Brain Res.2006; 1067:205-255.
[14]von Bohlen und Halbach O, Krause S, Medina D,et al, Regional and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies[J].Biol Psychiatry.2006;59: 793-800
[15]Li ZG, Zhang W, Grunberger G, et al. Hippocampal neuronal apoptosisin Type 1 diabetes[J]. Brain Res.2002; 946:221-231.
[16]王蓬文,杨芳,盛树力,等.胰岛素样生长因子受体-1在糖尿病小鼠脑内的分布[J].神经解剖学杂志.2002；18(2)：127-130.
[17]Watson GS, Cholerton BA, Reger MA, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone [J]. Am J Geriatr Psychiat.2005;13:950-958.
[18]J Am Med Assoe[J].2004; 292:2237-2242
[19]Vlassara H, Palace MR. Glycoxidation:the menace of diabetes and aging [J]. Mt Sinai J Med.2003; 70:232-241
[20]Wada-Isoe K, Wakutani Y, Urakami K et al.Elavated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients[J]. Acta Neurol Scand.2004; 110(2):124-127
[21]Jia JP,Meng R, Sun YX et al. Cerebrospinal fluid tau, Abetal-42 and inflammatory cytokines in patients with Alzheimer's disease and vascular dementia[J].Neurosci Lett.2005; 383(12):12-16
[22]Van Exel E,Gussekloo J, Remarque EJ. Ineraction of atherosclerosis and inflammation in elderly subjects with poor cognitive function [J]. Neurology.2003; 61(12):1605-1701
[23]Tarkowski E,Tullberg M, Fredman P et al. Corretation between intrathecal sulfatide and TNF-alpha levels in patients with vascular dementia[J]. Dement Geriatr Cogn Disord.2003; 15 (4):207-211
[24]Bowler J V. Vascular cognitive impairment advances in stroke 2003 [J]. Journal of the American Heart Association,2004; 35:386-388.
[25]Fouyas IP,Kelly PA,Ritchie IM, et al. Cerebrovascular responses to pathophysiological insulin in diabetic rats[J].J Clin Neurosci 2003; 10:88-91
[1]Riley KP, Snowdon DA, MarkesberyWR. Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study [J]. Ann Neurol.2002; 51 (5):567-577.
[2]Gong C X, Liu F, Iqbal K, et al. Post-translational modifications of tau protein in Alzheimer's disease[J]. J Neural Transm.2005; 112(6):813-838
[3]Dong Lei, Zhou Wen-Xia, Zhang Yong-Xiang.Abnormal post-translational modification of Tau protein and Alzheimer's disease[J]. Bulletin of the Academy of Military Medical Sciences.2006; 20 (1):76-79
[4]Gold M. Tau therapeutics for Alzheimer's disease:the promise and the challenges [J]. JMol neurosci.2002;19 (3):331-4
[5]Liu F, Iqbal K, Grundke-Iqbal I, et al. O-GlcNAcylation regulates phosphorylation of tau:a mechanism involved in alzheimer's disease [J] Proc Natl Acad Sci USA.2004; 101:10804-10809
[6]Lef ebvre T, Ferreira S, Dupont-Wallois L, et al. Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins-a role in nuclear localization[J]. Biochim Biophys Acta.2003; 1619(2):167-176.
[7]Tatebayashi Y, Haque N, Tung Y C, et al.Role of Tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport [J].J Cell Sci.2004; 117:1653-1663.
[8]Ebneth A, Godemann R, Stamer K, et al. Overexp ress ionof Tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria and endop lasmic reticulum:imp lications for Alzheimer's disease[J]. J Cell Biol.1998; 143(3):777-794
[9]Hua Q, He R Q, Haque N, et al. Microtubule associated p rotein tau binds to double-stranded but not single-stranded DNA[J]. CellMol Life Sci.2003; 60: 413-421.
[10]Bhaskar K, Yen S H, Lee G. Disease related modifications in tau affect the interaction between fyn and tau [J]. J Biol Chem.2005;280 (42):35119-35125.
[11]Hoffmann R, Leevm, Leight S, et al. Unique Alzheimer'sdisease paired helical filament specific ep itopes involve double phosphorylation at specific sites[J]. Biochemistry.1997; 36:8114-8124.
[12]Bussiere T, Hof P R, Maill lot C, et al. Delacourte a phosphorylated serine422 on tau p roteins is a pathological ep itope found in several diseases with neurofibrillary degeneration [J]. Acta Neuropathol (Berl). 1999; 97:221-230.
[13]Kepke E, Tung Y C, Sha Ikh S, et al. Microbutule associated protein tau: abnormal phosphorylation of a non2paired helical filament pool in alzheimer disease [J]. J Biol Chem.1993;268:24374-24384.
[14]Sengupta A, Kabat J, Novakm, et al. Maximal inhibition of tau binding tomicrotubules requires the phosphorylation of tau at both thr 231 and Ser 262 [J]. Neurobiol Aging.1998; (19S):S124-524.
[15]Schneider A, B iernat J, Von Bergenm, et al. Phosphorylation that detaches tau p rotein from microtubules (ser262, ser214) also p rotects it against aggregation into alzheimer paired helical filaments[J]. Biochemistry. 1999; 38:3549-3558.
[16]Alonso A, Del C, Mederl Yova A, et al. Promotion of hyperphosphorylation by frontotemporal dementia taumutations[J]. J Biol Chem.2004; 279: 34878-34881.
[17]Abraha A, Ghoshal N, Gambl In T C, et al. C-terminal inhibition of tau assembly in vitro and in alzheimer's disease [J]. J Cell Sci.2000; 113: 3737-3745.
[18]Haase C, Stieler J, Arend T T, et al. Pseudophosphorylation of tau p rotein alters its ability for self-aggregation[J]. J Neurochem.2004;88:1509-1520.
[19]Ferrar IA, Hoerndl I F, Baech I T, et al. Beta-amyloid induces paired helical filament-like tau filaments in tissue culture[J]. J Biol Chem. 2003;278:40162-40168.
[20]Hernandez F, Borrell J, Guaza C, et al.Spatial learning deficit in transgenic mice that conditionally over-exp ress gsk-3beta in the brain but do not form tau filaments [J]. J Neurochem.2002; 83:1529-1533.
[21]Lee V M Y, Kenyon T K, Trojonowski J Q1 Transgenic animalmodels of tauopathies[J]. Biochim Biophys Acta.2005; 1739 (223):251-259.
[22]Cheng Xin Gong, Fei Liu, Inge Grundke-Iqbal, et al. Dysregulation of Protein Phosphorylation/Dephosphorylation in Alzheimer's Disease:A Therapeutic Targe [J]. J Biomed Biotechnol.2006; 2006 (3):31825.
[23]Patrice Delobel, Isabelle Lavenir, Graham Fraser,et al. Analysis of Tau Phosphorylation and Truncation in a Mouse Model of Human Tauopathy Analysis of Mouse Tauopathy[J]. AJP January.2008; 172 (1),123-131
[24]Johnson G V, Stoothoffw H. Tau phosphorylation in neuronal cell function n dysfunction[J]. J Cell Sci.2004;117:5721-5729.
[25]Liu F, Grundke-Iqbal I, Iqbal K, et al. Contributions of protein phosph-atasesppl, pp2a, pp2b and pp5 to the regulation of tau phosphorylation [J]. Eur J Neurosci.2005; 22:1942-1950.
[26]Tanaka T, Zhong J, Iqbal K, et al.The regulation of phosphorylation of tau in sy5y neuroblastoma cells:the role of p rotein phosphatases [J]. FEBS Lett.1998; 426:248-254.
[27]Bennecib M, Gong C X, Grundke-Iqbal I, et al. Inhibition of PP-2A up regulates camkii in rat forebrain and induces hyperphosphorylation of tau at ser 262/356 [J].FEBS Lett.2001; 490:15-22.
[28]Pei J J, Gong C X, Anw, et al. Okadaic-acid-induced inhibition of p rotein phosphatase2a produces activation of mitogen-activated protein kinases erkl/2, mekl/2, and p70 s6, similar to that in alzheimer's disease[J]. Am J Pathol.2003; 163:845-858.
[29]Robertson L A, Moya KL, Breen K C. The potential role of tau p rotein o-glycosylation in alzheimer's disease [J]. J Alzheimer's Dis.2004; 6 (5): 489-495.
[30]Gong CX, Liu F, Grundke-Iqbal I, et al. Impaired brain glucose metabolism leads to alzheimer neurofibrillary degeneration through a decrease in tau o-GlcNAcylation[J].J Azheimer's Dis.2006; 9 (1):1-12.
[31]Hart G W. Dynamic 0-linked glycosylation of nuclear and cytoskeletal proteins [J]. Annu Biochem.1997; 66(1):315-335
[32]Hoyer S. Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease:therapeutic implications[J]. Adv Exp Med Biol.2004; 541:135-152
[33]Minoshima S, Frey K A, Koeppe R A, et al. A diagnostic approach in Alzheimer' s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET[J]. J Nucl Med.1995; 36 (7):1238-1248
[34]Hart G W, Greis K D, Dong L Y, et al.0-linked N-acetylgluc-osamine:the "yin-yang" of Ser/Thr phosphorylation Nuclear and cytoplasmic glycosy-lation[J]. Adv Exp Med Biol.1995; 376:115-123
[35]Planel E,Miyasaka T, Launey T, et al. Alterations in glucose metabolism induce hypothermia leading to tauhyperphosphorylation through different-tial inhibition of kinase and phosphatase activities:implications for Alzheimer's disease[J]. J Neurosci.2004; 24 (10):2401-2411
[36]Quinn CM, kagedal K, Terman A, et al. Induction of fibroblast apolipoprotein E expression during apoptosis, starvation-induced growth arrest and mitosis[J]. Biochem J.2004; 378 (3):753-761.
[37]石俊,李旭,卢芬.饥饿对小鼠脑中tau蛋白磷酸化和O-GlcNAc糖基化的影响[J].生物化学与生物物理进展.2006;33(7)：647-652.
[38]Liu Y, Liu F, Iqbal K, et al. Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer's disease [J]. FEBS Lett.2008; 582 (2):359-364.
[39]Dias,W B; Hart,G W.O-GlcNAc modification in diabetes and Alzheimer's disease[J]. Mol-Biosyst.2007; 3(11):766-772
[40]Tallent,M K; Varghis,N; Skorobogatko, Y,et al. In Vivo Modulation of O-GlcNAc Levels Regulates Hippocampal Synaptic Plasticity through Interplay with Phosphorylation[J]. J-Biol-Chem.2009; 284(1):174-181
[41]Yuzwa, S A; Macauley,M S; Heinonen, J E, et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo[J]. Nat-Chem-Biol.2008; 4(8):483-490