督脉不同电针对拟AD模型-SAMP8小鼠额叶Aβ代谢途径的影响
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摘要
1研究目的
     AD是临床痴呆最主要的类型,以进行性神经变性为特征,在疾病的某一阶段还常伴有明显的精神行为异常,严重损伤患者的生活能力和社会功能,同时给家庭和社会亦带来沉重负担,已成为当今老年医学面临的最为严峻的问题之一。综合以往研究,关于AD病理机制存在多种假说,每种假说都与AD大脑一些重要生物化学成分改变相关,特别是涉及重要蛋白质和酶等生物大分子的改变。其中,β-淀粉样蛋白(Ap)假说得到广泛认可,该假说认为Aβ是AD发病的关键环节,其毒性引发的连锁反应是AD一系列病理改变的基础。因此,有效抑制Aβ分泌,干扰Ap毒性引发的连锁反应,打断其恶性循环是治疗AD的一个重要策略。
     依据导师李志刚教授长期临床经验并且结合前期动物实验研究发现,通督启神针法能够促进神经细胞修复再生,有效改善脊髓损伤、颅脑损伤等与中枢神经系统相关疾病,是一种实用性较强的治疗方法。临床AD具有心理学特性,以往将传统针刺疗法与音乐疗法结合治疗AD的研究尚不多见。本研究以与AD发病密切相关的Aβ蛋白为切入点,首次将音乐电针疗法作为一种干预手段引入AD的治疗中,采用神经行为学、分子生物学等方法,深入探讨通督启神针法指导下的不同电针对AD模型小鼠额叶皮层Aβ蛋白生成途径和清除途径两方面的影响,同时对比分析脉冲电针与音乐电针的疗效差异,以期为临床应用音乐电针治疗AD以及其他脑相关疾病提供科学实验依据。
     2研究方法
     本研究采用动物实验方法,以SAMR1和SAMP8小鼠作为研究对象,分为空白对照组(B组)、模型对照组(C组)、药物对照组(D组)、音乐对照组(M组)、音乐电针组(ME组)和脉冲电针组(PE组)6个组别,干预15天后,采用Morris水迷宫实验评估各组小鼠行为学的变化,比较不同电针对学习记忆能力的影响;采用尼氏染色观察各组小鼠额叶皮层神经细胞的病理改变,比较不同电针对细胞形态学的影响;采用免疫组织化学方法和Western Blot方法检测各组小鼠额叶皮层Aβ40和BACE1含量,并应用Real time-PCR法检测BACE1mRNA表达情况,比较不同电针对Aβ生成途径的影响;采用免疫组织化学方法和Western Blot方法检测各组小鼠额叶皮层Aβ降解酶IDE、 NEP以及相关转运受体LRP1、RAGE的表达情况,比较不同电针对Aβ清除途径的影响。
     3研究结果
     3.1定位航行实验中,与B组比较,C组小鼠逃避潜伏期基线较高,而且经过5天训练并没有明显缩短,同时游泳总路程基线较低,并且有持续下降趋势。D组、ME组和PE组逃避潜伏期随训练时间增加呈波动性下降趋势,以ME组尤为突出,其出现明显变化时间最早,随后出现明显变化的是D组、PE组,而M组在5天的训练中变化并不明显。在游泳总路程上ME组与C组比较,具有显著性差异,且在某些时间点上优于D组和PE组。在空间探索实验中,与B组比较,C组原平台象限停留时间及游泳路程显著下降,搜索策略多呈随机式,无明显倾向性,而D组、ME组和PE组与C组比较有明显差异,搜索多停留在原平台所在象限或附近,ME组与D组无显著性差异,略优于PE组。
     3.2B组额叶皮层的神经元体积较大,形态规则,胞浆内布满尼氏体,呈深蓝色。C组额叶皮层的神经元体积较小,形态不规则,有较多细胞失去完整形态,神经元胞浆内尼氏体着色浅淡,有一定程度的脱失。经不同电针及药物干预的治疗组额叶皮层的神经元体积大于C组,但明显小于B组,形态较规则,胞浆内尼氏体有一定程度的恢复。M组较C组形态学无显著性变化。
     3.3与B组比较,C组Aβ40表达明显升高,差异具有显著性。与C组比较,D组、ME组、PE组Aβ40表达水平均明显下降,但M组无显著性变化。与D组比较,ME组Aβ40表达水平无明显差异,PE组和M组仍明显增高。ME组Aβ40水平与PE组无显著差异。
     3.4与B组比较,C组小鼠额叶皮层BACE1mRNA相对表达量及BACE1表达水平明显升高。与C组比较,D组、ME组、PE组两指标均有不同程度下调,差异具有显著性,其中ME组与D组作用相当,且略强于PE组,而M组无明显变化。
     3.5与B组比较,C组IDE、NEP含量均明显降低,差异具有显著性。与C组比较,D组、ME组、PE组两指标表达水均有不同程度提高。在提高IDE表达方面,ME组优于D组和PE组,而在改善NEP表达方面,ME组与PE组无显著性差异,且稍逊于D组。M组两指标的变化无统计学意义。
     3.6与B组比较,C组LRP1表达水平明显下降,而RAGE明显升高,差异具有显著性。与C组比较,ME组和PE组两指标的表达水平均明显改善,差异具有统计学意义,且ME优于PE,而D组和M组在两个指标的表达上与C组相比无显著性差异。
     4研究结论
     4.1通督启神针法指导下的电针疗法对拟AD模型——SAMP8小鼠学习记忆障碍具有改善作用。
     4.2通督启神针法指导下的电针疗法可修复AD模型——SAMP8小鼠额叶皮层神经细胞的损伤,对神经细胞具有一定的保护作用,并且可以通过纠正Ap代谢障碍,降低Aβ40的表达水平,从而发挥治疗痴呆的作用。
     4.3通督启神针法指导下的电针疗法发挥纠正Aβ代谢障碍的作用,通过两条途径实现:第一,干预Aβ生成途径。电针通过抑制BACE1表达,减少APP通过淀粉样蛋白源性加工途径产生Aβ;第二,干预Ap清除途径。电针通过增加IDE、NEP等Ap降解酶表达,双向调节Ap蛋白相关转运体LRP1及RAGE水平,促进脑内Aβ降解及转运。
     4.4音乐电针和脉冲电针均可通过改善神经细胞损伤和纠正Ap代谢障碍,从而促进拟AD模型——SAMP8小鼠学习记忆能力恢复。虽然在下调Aβ40和保护神经细胞方面,音乐电针相对于脉冲电针的优势没有统计学意义,但是在改善行为学及大部分Aβ相关降解酶和转运受体方面,音乐电针的优越性得以体现。综合行为学结果及与Ap代谢相关的分子生物学指标,音乐电针疗法的作用最全面。
1Objectve
     Alzheimer's disease (AD) is the most common type of clinical dementia, characterized by progressive neurodegenerative, and often accompanied by significant mental and behavioral abnormalities in the certain stage. It seriously affects the life ability and social function of the patient, at the same time also brings heavy burden to family and society, which has become one of the most serious problems facing geriatric medicine today. Comprehensive previous research, there are many hypotheses about AD pathological mechanism, each hypothesis associated with some important biological chemical composition in brain, especially the important biological macromolecules such as protein and enzymes involved in the biochemistry change. At present, β-amyloid(Aβ)pothesis is widely recognized, which points that AP is the key to the pathogenesis of AD, and the chain reaction caused by its toxicity is the basis of pathological changes in AD. Therefore, an important strategy for the treatment of AD is interrupting the vicious cycle caused by Aβ,by means of restraining Aβ secretion and deposition and disturbing the chain reaction caused by its toxicity in the multi-link and multi-path effectively.
     Professor Li Zhigang based long-term clinical experience combined with previous animal experiments summarized Dredging Governor Meridian and Awakening Mind Method. It is a kind of practical treatment, which can effectively improve the diseases associated with central nervous system by promoting nerve cell regeneration, such as spinal cord injuries and traumatic brain injury. AD has a characteristic of psychology, yet the research about combining the traditional acupuncture and music therapy in the treatment of AD is still rare in the past. This study is based on β-amyloid hypothesis, with Aβ as the breakthrough point, at the same time including music therapy as an intervention to the treatment of AD. We will delve into different electro-acupuncture treatment guided by Dredging Governor Meridian and Awakening Mind Method for Aβ production means and clear way in frontal cortex of AD model, as well as Compare the curative effect of pulse electro-acupuncture and music electro-acupuncture differences, in order to provide a scientific basis for its clinical application of music electro-acupuncture treatment of AD and other brain-related diseases.
     2Methods
     In this study, SAMR1and SAMP8mice were used as the research object. They were randomly divided into blank control group (B group), model control group(C group), drug control group(D group), music control group(M group), pulse electro-acupuncture group (PE group) and music electro-acupuncture group(ME group). Morris Water Maze Test was used to detected the learning memory ability of mice, and then compared the influence of two kinds of electro-acupuncture therapy for the ability of learning and memory; Nissl staining was used to observe the pathological changes of mice frontal cortex neurons, and then compared the effect of different therapy; Immunohistochemistry and western blot were used to assay the expression levels of Aβ40and BACE1in frontal cortex, as well as Real-time PCR was used to measure the expression of BACElmRNA, so as to compare the effect of different therapy for Aβ generation; Immunohistochemistry and western blot were used to assay the expression levels of IDE, NEP, LRP1and RAGE in frontal cortex, so as to compare the effect of different therapy for Aβ clearance.
     3Results
     3.1Compared with B group, escape latency period baseline was higher and it was not significantly reduced after five days training, as well as total distance of swimming baseline was lower and continued to drop in C group. Escape latency period in groups of D, ME and PE shortened with the increase of training time, especially ME group, but it did not change significantly in M group. Total distance of swimming in ME group was significantly longer than in C group, also longer than D and PE group in some points. In the experiment of space exploration, Search strategy in C group was mostly random and with no obvious bias, as well as the original platform quadrant residence time and swimming distance dropped significantly compared with B group; D, ME and PE groups were better than C group, and ME group was the same as D group but a litter better than PE group.
     3.2Nissl staining showed frontal cortex pyramidal cells in B group arranged closely and orderly. But in C group, the pyramidal cells in frontal cortex was disorganized or wrinkled like, even incomplete form. Moreover, the number decreased significantly. In addition to the M group, the situation in groups of D, ME and PE were better than in C group.
     3.3Compared with B group, Aβ40expression level of frontal cortex in C group was significantly increased. Compared with C group, it was decreased obviously in groups of D, ME and PE except M group. Compared with D group, ME group was no significant difference, but PE and M groups were still significantly higher than it. There was no significant difference in Aβ40levels between ME group and PE group.
     3.4Compared with B group, BACE1mRNA relative expression and BACE1expression levels of frontal cortex in C group were significantly increased. Compared with C group, both in groups of D, ME and PE had different degrees of reduction and the difference was significant. ME group was the same as D group but a litter better than PE group.
     3.5Compared with B group, expression level of IDE and NEP in frontal cortex in C group was significantly decreased. Compared with C group, both in groups of D, ME and PE had a certain degree of improvement. ME group was better than D and PE groups in terms of regulating the expression of IDE, and there was no significant difference in regulating the expression of NEP between ME group and PE group, but both were not as good as D group. Both IDE and NEP in M group were not statistically significant.
     3.6Compared with B group, expression level of LRP1in frontal cortex in C group was significantly decreased, but RAGE significantly increased. Compared with C group, both in ME group and PE group were significantly improved, and ME group better than PE group. However, both LRP1and RAGE in groups of D and M were No obvious change.
     4Conclusions
     4.1Both pulse electro-acupuncture and music electro-acupuncture treatment guided by Dredging Governor Meridian and Awakening Mind Method can improve the learning and memory disorders of S AMP8mice with AD feature.
     4.2Both pulse electro-acupuncture and music electro-acupuncture treatment guided by Dredging Governor Meridian and Awakening Mind Method can repair the damage to the frontal cortex neurons of SAMP8mice with AD feature, thus play a role in protecting neurons. In addition, they can reduce the expression levels of Aβ40and correct Aβ metabolic disorder. So they have a role in the treatment of AD.
     4.3Electro-acupuncture treatment guided by Dredging Governor Meridian and Awakening Mind Method play a role in correcting A(3metabolic disorders through two ways. On the one hand, it can restrain the generation of A(3by reducing the expression levels of BACE1;on the other hand, it can promote the clearance of Aβ by increasing the expression levels of IDE and NEP which belong to Aβ degrading enzyme and regulate the content of LRP1and RAGE which belong to A(3protein related transporters.
     4.4By means of repairing the damage to neurons and correcting Aβ metabolic disorders in the frontal cortex, both pulse electro-acupuncture and music electro-acupuncture treatment guided by Dredging Governor Meridian and Awakening Mind Method can improve the learning and memory disorders of SAMP8mice with AD feature. There is no difference between the two treatments in adjusting individual indicators, but music electro-acupuncture treatment has more advantage on the whole.
引文
[1]王晶.我国阿尔茨海默病的流行现状及预防措施[J].亚太传统医药.2011.(02):157-158.
    [2]Hashimoto M, Rockenstein E, Crews L, Masliah E. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases[J]. Neuromolecular Med.2003.4(1-2):21-36.
    [3]Ineichen B. The geography of dementia:an approach through epidemiology[J]. Health Place. 1998.4(4):383-94.
    [4]Hendrie HC. Epidemiology of Alzheimer's disease[J]. Geriatrics,1997.52 Suppl 2:S4-8.
    [5]屈秋民,乔晋,杨剑波等.西安地区中老年人的痴呆患病率调查[J].中华老年医学杂志.2001.(04):42-45.
    [6]张振馨,ZahnerGE, RomanGC等.中国北京、西安、上海和成都地区痴呆亚型患病率的研究[J].中国现代神经疾病杂志.2005.(03):156-157.
    [7]汤哲.北京地区老年痴呆流行病学研究[J].中华流行病学杂志.2003.(08):90-92.
    [8]Zhang ZX, Zahner GE, Roman GC, et al. Dementia subtypes in China:prevalence in Beijing, Xian, Shanghai, and Chengdu[J]. Archives of neurology.2005.62(3):447-53.
    [9]薛冠华,邵也常,朱高章等.广东省老年痴呆流行病学研究[J].实用医学杂志.1997.(06):371-2.
    [10]张京立,张红红,陶国枢等.北京海淀区1390名老年人老年期痴呆流行病调查[J].中华流行病学杂志.1998.(01):20-22.
    [11]唐牟尼,刘协和,邹晓毅等.成都地区老年期痴呆患病率调查[J].中华精神科杂志.2001.(04):37-41.
    [12]栗克清,江琴普,崔利军等.河北省城乡老年性痴呆的流行病学调查[J].中国健康心理学杂志.2008.(11):1251-53.
    [13]范俭雄,言镜玲,陈震华等.南京地区老年期痴呆流行病学调查[J].临床精神医学杂志.2000.(03):137-8.
    [14]丁玎,赵倩华,郭起浩等.上海城区老年性痴呆患病率调查[J].中国临床神经科学.2013.(01):19-25.
    [15]张振馨,魏镜,洪霞等.北京市城乡痴呆及其主要亚型的患病率[J].中华神经科杂志.2001.(04):7-11.
    [16]Jorm AF, Jolley D. The incidence of dementia:a meta-analysis. Neurology[J].1998.51(3): 728-33.
    [17]Matthews F, Brayne C. The incidence of dementia in England and Wales:findings from the five identical sites of the MRC CFA Study[J]. PLoS Med.2005.2(8):e193.
    [18]张明园,陈佩俊,何燕玲等.痴呆和阿尔茨海默病的发病率[J].中华精神科杂志.1998.(04):3-6.
    [19]陈曦,黄东锋,林爱华等.广东省成人精神残疾主要致残原因和对策分析[J].中国康复医学杂志.2009.(10):938-41.
    [20]朱紫青,张明园.社区老年人5年随访中痴呆等疾病的死亡率分析[J].中华精神科杂志.1997.(04):40-43.
    [21]Fitzpatrick AL, Kuller LH, Lopez OL, Kawas CH, Jagust W. Survival following dementia onset:Alzheimer's disease and vascular dementia[J]. J Neurol Sci.2005.229-230:43-9.
    [22]Middleton LE, Grinberg LT, Miller B, Kawas C, Yaffe K. Neuropathologic features associated with Alzheimer disease diagnosis:age matters[J]. Neurology.2011.77(19): 1737-44.
    [23]刘爽,张玉莲,周震.老年性痴呆流行病学研究现况[J].中国老年学杂志.2010.(10):1455-7.
    [24]Singh M, Simpkins JW, Simpkins JW, et al. Window of opportunity for estrogen and progestin intervention in brain aging and Alzheimer's disease[J]. Brain Res.2013.1514:1-2.
    [25]Rongve A, Arsland D, Graff C. [Alzheimer's disease and genetics]. Tidsskrift for den Norske laegeforening:tidsskrift for praktisk medicin, ny raekke [J].2013.133(14):1449-52.
    [26]Antonell A, Llado A, Altirriba J, et al. A preliminary study of the whole-genome expression profile of sporadic and monogenic early-onset Alzheimer's disease[J]. Neurobiol Aging.2013. 34(7):1772-8.
    [27]Nelson O, Supnet C, Liu H, Bezprozvanny I. Familial Alzheimer's disease mutations in presenilins:effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes [J]. J Alzheimers Dis.2010.21(3):781-93.
    [28]Ikeda T, Yamada M. [Risk factors for Alzheimer's disease]. Brain and nerve[J] Shinkei kenkyu no shinpo.2010.62(7):679-90.
    [29]Buee L, Hof PR, Bouras C, et al. Pathological alterations of the cerebral microvasculature in Alzheimer's disease and related dementing disorders [J]. Acta Neuropathol.1994.87(5): 469-80.
    [30]Irie F, Fitzpatrick AL, Lopez OL, et al. Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4:the Cardiovascular Health Study Cognition Study [J]. Archives of neurology.2008.65(1):89-93.
    [31]Khachaturian AS, Zandi PP, Lyketsos CG, et al. Antihypertensive medication use and incident Alzheimer disease:the Cache County Study [J]. Archives of neurology.2006.63(5):686-92.
    [32]Irie F, Fitzpatrick AL, Lopez OL, et al. Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4:the Cardiovascular Health Study Cognition Study [J]. Archives of neurology.2008.65(1):89-93.
    [33]韩恩吉.实用痴呆学[M].济南:山东科学技术出版社,2011,313-15.
    [34]Solito E, Sastre M. Microglia function in Alzheimer's disease [J]. Front Pharmacol.2012.3: 14.
    [35]Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease [J]. N Engl J Med Overseas Ed.2003.348(14):1356-64.
    [36]Postina R, Schroeder A, Dewachter I, et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model [J]. J Clin Invest.2004.113(10):1456-64.
    [37]De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma secretase complex [J]. Neuron.2003.38(1):9-12.
    [38]Nyabi O, Bentahir M, Horre K, et al. Presenilins mutated at Asp-257 or Asp-385 restore Pen-2 expression and Nicastrin glycosylation but remain catalytically inactive in the absence of wild type Presenilin[J]. J Biol Chem.2003.278(44):43430-6.
    [39]Kamboh MI. Molecular genetics of late-onset Alzheimer's disease [J]. Ann Hum Genet.2004. 68(Pt 4):381-404.
    [40]Barghorn S, Zheng-Fischhofer Q, Ackmann M, et al. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry [J].2000.39(38):11714-21.
    [41]Rosenberg RN. The molecular genetics of neurological disease [J]. Recent advances. Neurologia(Barcelona, Spain).1993.8(5):116-23.
    [42]Wavrant-DeVrieze F, Perez-Tur J, Lambert JC, et al. Association between the low density lipoprotein receptor-related protein (LRP) and Alzheimer's disease[J]. Neurosci Lett.1997. 227(1):68-70.
    [43]Holtzman DM, Pitas RE, Kilbridge J, et al. Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line[J]. Proc Natl Acad Sci U S A.1995.92(21):9480-4.
    [44]Bertram L, Hiltunen M, Parkinson M, et al. Family-based association between Alzheimer's disease and variants in UBQLN1. N Engl J Med Overseas Ed[J].2005.352(9):884-94.
    [45]Xue WG, Zhang Z, Bai LM, Xu H, Wu HX. [Effect of electroacupuncture on the behavior and the expression of amyloid beta-protein, amyloid precursor protein and ChAT in APP 695 V 717 I transgenic mice] [J]. Zhen ci yan jiu -Acupuncture research/[Zhongguo yi xue ke xue yuan Yi xue qing bao yan jiu suo bian ji].2009.34(3):152-8.
    [46]Huagn Y, Xu YM, Zhang JW, Ren XH, Suo AQ. [Effects of estrogen on P-Tau, ChAT and nerve growth factor protein expressions in the brain tissue of rats with Alzheimer's disease] [J]. Nan fang yi ke da xue xue bao -Journal of Southern Medical University.2010.30(10): 2408-10.
    [47]Harold D, Macgregor S, Patterson CE, et al. A single nucleotide polymorphism in CHAT influences response to acetylcholinesterase inhibitors in Alzheimer's disease[J]. Pharmacogenet Genomics.2006.16(2):75-77.
    [48]Piccardi M, Congiu D, Squassina A, et al. Alzheimer's disease:case-control association study of polymorphisms in ACHE, CHAT, and BCHE genes in a Sardinian sample[J]. Am J Med Genet B Neuropsychiatr Genet.2007.144B(7):895-9.
    [49]Cunningham C. Microglia and neurodegeneration:The role of systemic inflammation [J]. Glia 2013; 61(1):71-90.
    [50]Weitz TM, Town T. Microglia in Alzheimer's Disease:It's All About Context [J]. Int J Alzheimers Dis.2012:314185.
    [51]Solito E, Sastre M. Microglia function in Alzheimer's disease [J]. Front Pharmacol.2012.3: 14.
    [52]Poorkaj P, Kas A, D'Souza I, et al. A genomic sequence analysis of the mouse and human microtubule-associated protein tau [J]. Mamm Genome.2001.12(9):700-12.
    [53]Ahlijanian MK, Barrezueta NX, Williams RD, et al. Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5[J]. Proc Natl Acad Sci U S A.2000.97(6):2910-5.
    [54]Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A. Tau is essential to beta-amyloid-induced neurotoxicity [J]. Proc Natl Acad Sci U S A.2002.99(9):6364-9.
    [55]Neve RL, McPhie DL. Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis [J]. Biochim Biophys Acta.2007.1772(4):430-7.
    [56]Langley B, Ratan RR. Oxidative stress-induced death in the nervous system:cell cycle dependent or independent [J]. J Neurosci Res.2004.77(5):621-9.
    [57]Yang Y, Varvel NH, Lamb BT, Herrup K. Ectopic cell cycle events link human Alzheimer's disease and amyloid precursor protein transgenic mouse models[J]. J Neurosci.2006.26(3): 775-84.
    [58]Tei H, Miyazaki A, Iwata M, Osawa M, Nagata Y, Maruyama S. Early-stage Alzheimer's disease and multiple subcortical infarction with mild cognitive impairment: neuropsychological comparison using an easily applicable test battery[J]. Dement Geriatr Cogn Disord.1997.8(6):355-8.
    [59]Daly E, Zaitchik D, Copeland M, Schmahmann J, Gunther J, Albert M. Predicting conversion to Alzheimer disease using standardized clinical information[J]. Archives of neurology.2000. 57(5):675-80.
    [60]Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer's disease:revising the NINCDS-ADRDA criteria[J]. Lancet Neurol.2007.6(8):734-46.
    [61]Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease[J]. Donepezil Study Group. Neurology.1998.50(1):136-45.
    [62]Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer's disease:double-blind, parallel-group, placebo-controlled study[J]. Lancet.2006.367(9516): 1057-65.
    [63]Allain H, Bentue-Ferrer D, Zekri O, Schuck S, Lebreton S, Reymann JM. Experimental and clinical methods in the development of anti-Alzheimer drugs[J]. Fundam Clin Pharmacol. 1998.12(1):13-29.
    [64]Jain KK. Evaluation of memantine for neuroprotection in dementia[J]. Expert Opin Investig Drugs.2000.9(6):1397-406.
    [65]Dodel RC, Du Y, Depboylu C, et al. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease[J]. J Neurol Neurosurg Psychiatry.2004.75(10):1472-4.
    [66]Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease:a randomised phase Ⅱ trial[J]. Lancet Neurol.2008.7(6):483-93.
    [67]Lannfelt L, Blennow K, Zetterberg H, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease:a phase Ila, double-blind, randomised, placebo-controlled trial[J]. Lancet Neurol.2008.7(9):779-86.
    [68]Bulic B, Pickhardt M, Schmidt B, Mandelkow EM, Waldmann H, Mandelkow E. Development of tau aggregation inhibitors for Alzheimer's disease[J]. Angewandte Chemie (International ed. in English).2009.48(10):1740-52.
    [69]Zhang YW, Chen Y, Liu Y, Zhao Y, Liao FF, Xu H. APP regulates NGF receptor trafficking and NGF-mediated neuronal differentiation and survival[J]. PLoS One.2013.8(11):e80571.
    [70]Nelson AR, Kolasa K, McMahon LL. Noradrenergic sympathetic sprouting and cholinergic reinnervation maintains non-amyloidogenic processing of AbetaPP[J]. J Alzheimers Dis. 2014.38(4):867-79.
    [71]Chen Q, Zhou Z, Zhang L, Xu S, Chen C, Yu Z. The cellular distribution and ser262 phosphorylation of tau protein are regulated by BDNF in vitro[J]. PLoS One.2014.9(3): e91793.
    [72]Chow TW, Pollock BG, Milgram NW. Potential cognitive enhancing and disease modification effects of SSRIs for Alzheimer's disease[J]. Neuropsychiatr Dis Treat.2007. 3(5):627-36.
    [73]Zhang W, Wang GM, Wang PJ, Zhang Q, Sha SH. Effects of neural stem cells on synaptic proteins and memory in a mouse model of Alzheimer's disease[J]. J Neurosci Res.2014. 92(2):185-94.
    [74]Chen SQ, Cai Q, Shen YY, Wang PY, Li MH, Teng GY. Neural Stem Cell Transplantation Improves Spatial Learning and Memory via Neuronal Regeneration in Amyloid-beta Precursor Protein/presenilin 1/tau Triple Transgenic Mice[J]. Am J Alzheimers Dis Other Demen.2014.29(2):142-9.
    [75]郝春光,习杨彦彬,刘佳,戴萍,王廷华SCN2b mRNA在快速老化小鼠额叶和海马中的表达及变化[J].神经解剖学杂志.2007.(06):662-5.
    [76]Chen SC, Lu G, Chan CY, et al. Microarray profile of brain aging-related genes in the frontal cortex of SAMP8[J]. J Mol Neurosci.2010.41(1):12-6.
    [77]Luu P, Caggiano DM, Geyer A, Lewis J, Cohn J, Tucker DM. Time-course of cortical networks involved in working memory[J]. Front Hum Neurosci.2014.8:4.
    [78]Wilson RC, Takahashi YK, Schoenbaum G, Niv Y. Orbitofrontal cortex as a cognitive map of task space[J]. Neuron.2014.81(2):267-79.
    [79]Leung HC, Gore JC, Goldman-Rakic PS. Sustained mnemonic response in the human middle frontal gyrus during on-line storage of spatial memoranda[J]. J Cogn Neurosci.2002.14(4): 659-71.
    [80]Du BF, Levy R, Volle E, et al. Functions of the left superior frontal gyrus in humans:a lesion study[J]. Brain.2006.129(Pt 12):3315-28.
    [81]Becker B, Androsch L, Jahn RT, et al. Inferior frontal gyrus preserves working memory and emotional learning under conditions of impaired noradrenergic signaling[J]. Front Behav Neurosci.2013.7:197.
    [82]Kao SC, Huang CJ, Hung TM. Frontal midline theta is a specific indicator of optimal attentional engagement during skilled putting performance[J]. J Sport Exerc Psychol.2013. 35(5):470-8.
    [83]Weissman DH, Carp J. The congruency effect in the posterior medial frontal cortex is more consistent with time on task than with response conflict [J]. PLoS One.2013.8(4):e62405.
    [84]Phillips S, Takeda Y, Singh A. Visual feature integration indicated by pHase-locked frontal-parietal EEG signals [J]. PLoS One.2012.7(3):e32502.
    [85]Berchio C, Rihs TA, Michel CM, et al. Parieto-frontal circuits during observation of hidden and visible motor acts in children. A high-density EEG source imaging study [J]. Brain Topogr. 2014.27(2):258-70.
    [86]Selkoe DJ. Amyloid protein and Alzheimer's disease[J]. Sci Am.1991.265(5):68-71,74-6, 78.
    [87]Glenner GG, Wong CW. Alzheimer's disease:initial report of the purification and characterization of a novel cerebrovascular amyloid protein[J]. Biochem Biophys Res Commun.1984.120(3):885-90.
    [88]Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome[J]. Proc Natl Acad Sci U S A. 1985.82(12):4245-9.
    [89]Tanzi RE, Moir RD, Wagner SL. Clearance of Alzheimer's Abeta peptide:the many roads to perdition [J]. Neuron.2004.43(5):605-8.
    [90]Hornsten A, Lieberthal J, Fadia S, et al. APL-1, a Caenorhabditis elegans protein related to the human beta-amyloid precursor protein, is essential for viability [J]. Proc Natl Acad Sci U S A.2007.104(6):1971-6.
    [91]Ting JT, Kelley BG, Lambert TJ, Cook DQ Sullivan JM. Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms [J]. Proc Natl Acad Sci U S A.2007.104(1):353-8.
    [92]Haass C. Take five--BACE and the gamma-secretase quartet conduct Alzheimer's amyloid beta-peptide generation [J]. EMBO J.2004.23(3):483-8.
    [93]Mastrangelo IA, Ahmed M, Sato T, et al. High-resolution atomic force microscopy of soluble Abeta42 oligomers [J]. J Mol Biol.2006.358(1):106-19.
    [94]Roychaudhuri R, Yang M, Hoshi MM, Teplow DB. Amyloid beta-protein assembly and Alzheimer disease. J Biol Chem [J].2009.284(8):4749-53.
    [95]Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics [J]. Science (New York, N.Y.).2002.297(5580):353-6.
    [96]Renbaum P, Levy-Lahad E. Monogenic determinants of familial Alzheimer's disease: presenilin-2 mutations [J]. Cell Mol Life Sci.1998.54(9):910-9.
    [97]Kayed R, Sokolov Y, Edmonds B, et al. Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases[J]. J Biol Chem.2004.279(45):46363-6.
    [98]Lomakin A, Teplow DB, Kirschner DA, Benedek GB. Kinetic theory of fibrillogenesis of amyloid beta-protein [J]. Proc Natl Acad Sci U S A.1997.94(15):7942-7.
    [99]Harper JD, Wong SS, Lieber CM, Lansbury PT Jr. Assembly of A beta amyloid protofibrils: an in vitro model for a possible early event in Alzheimer's disease[J]. Biochemistry.1999. 38(28):8972-80.
    [100]Iwatsubo T. The gamma-secretase complex:machinery for intramembrane proteolysis [J]. Curr Opin Neurobiol.2004.14(3):379-83.
    [101]Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2[J]. Proc Natl Acad Sci U S A.2003.100(11):6382-7.
    [102]De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex [J]. Neuron.2003.38(1):9-12.
    [103]Fraering PC, Ye W, Strub JM, et al. Purification and characterization of the human gamma-secretase complex. Biochemistry [J].2004.43(30):9774-89.
    [104]Periz G, Fortini ME. Functional reconstitution of gamma-secretase through coordinated expression of presenilin, nicastrin, Aph-1, and Pen-2[J]. J Neurosci Res.2004.77(3):309-22.
    [105]Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein [J]. Proc Natl Acad Sci U S A.2000.97(4):1456-60.
    [106]Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity [J]. Nature.1999.402(6761):533-7.
    [107]Liu K, Doms RW, Lee VM. Glull site cleavage and N-terminally truncated A beta production upon BACE overexpression [J]. Biochemistry.2002.41(9):3128-36.
    [108]Cai H, Wang Y, McCarthy D, et al. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons[J]. Nat Neurosci.2001.4(3):233-4.
    [109]Luo Y, Bolon B, Kahn S, et al. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation [J]. Nat Neurosci.2001.4(3): 231-2.
    [110]Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice[J]. Science (New York, N.Y.).1996.274(5284):99-102.
    [111]Harrison SM, Harper AJ, Hawkins J, et al. BACE1 (beta-secretase) transgenic and knockout mice:identification of neurochemical deficits and behavioral changes [J]. Mol Cell Neurosci. 2003.24(3):646-55.
    [112]Hu X, Hicks CW, He W, et al. Bacel modulates myelination in the central and peripheral nervous system[J]. Nat Neurosci.2006.9(12):1520-5.
    [113]Sankaranarayanan S, Holahan MA, Colussi D, et al. First demonstration of cerebrospinal fluid and plasma A beta lowering with oral administration of a beta-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates[J]. J Pharmacol Exp Ther.2009. 328(1):131-40.
    [114]Von ACA, Kinoshita A, Peltan ID, et al. The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate [J]. J Biol Chem.2005.280(18): 17777-85.
    [115]Yan R, Han P, Miao H, Greengard P, Xu H. The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta -amyloid precursor protein (APP) substrate [J]. J Biol Chem.2001.276(39):36788-96.
    [116]Selkoe DJ. Alzheimer's disease:genes, proteins, and therapy [J]. Physiol Rev.2001.81(2): 741-66.
    [117]Postina R, Schroeder A, Dewachter I, et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model [J]. J Clin Invest.2004.113(10):1456-64.
    [118]Cirrito JR, May PC, O'Dell MA, et al. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life[J]. J Neurosci.2003.23(26):8844-53.
    [119]Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA. The production of amyloid beta peptide is a critical requirement for the viability of central neurons [J]. J Neurosci.2003.23(13): 5531-5.
    [120]Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration:lessons from the Alzheimer's amyloid beta-peptide [J]. Nat Rev Mol Cell Biol.2007.8(2):101-12.
    [121]Oddo S, Vasilevko V, Caccamo A, Kitazawa M, Cribbs DH, LaFerla FM. Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles [J]. J Biol Chem.2006.281(51):39413-23.
    [122]Lesne S, Koh MT, Kotilinek L, et al. A specific amyloid-beta protein assembly in the brain impairs memory[J]. Nature.2006.440(7082):352-7.
    [123]Forloni G, Chiesa R, Smiroldo S, et al. Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25-35[J]. Neuroreport.1993.4(5):523-6.
    [124]Ohyagi Y, Asahara H, Chui DH, et al. Intracellular Abeta42 activates p53 promoter:a pathway to neurodegeneration in Alzheimer's disease [J]. FASEB J.2005.19(2):255-7.
    [125]Cotman CW, Anderson AJ. A potential role for apoptosis in neurodegeneration and Alzheimer's disease [J]. Mol Neurobiol.1995.10(1):19-45.
    [126]Smale G, Nichols NR, Brady DR, Finch CE, Horton WE Jr. Evidence for apoptotic cell death in Alzheimer's disease [J]. Exp Neurol.1995.133(2):225-30.
    [127]Zhang Y, McLaughlin R, Goodyer C, LeBlanc A. Selective cytotoxicity of intracellular amyloid beta peptide 1-42 through p53 and Bax in cultured primary human neurons[J]. J Cell Biol.2002.156(3):519-29.
    [128]Ferreiro E, Oliveira CR, Pereira C. Involvement of endoplasmic reticulum Ca2+ release through ryanodine and inositol 1,4,5-triphosphate receptors in the neurotoxic effects induced by the amyloid-beta peptide [J]. J Neurosci Res.2004.76(6):872-80.
    [129]Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells [J]. J Cell Biol.2003.161(1):41-54.
    [130]Lustbader JW, Cirilli M, Lin C, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease [J]. Science (New York, N.Y.).2004.304(5669):448-52.
    [131]Cavallucci V, Ferraina C, D'Amelio M. Key role of mitochondria in Alzheimer's disease synaptic dysfunction [J]. Curr Pharm Des.2013.19(36):6440-50.
    [132]Calkins MJ, Reddy PH. Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer's disease neurons [J]. Biochim Biophys Acta.2011. 1812(4):507-13.
    [133]Barnham KJ, Cappai R, Beyreuther K, Masters CL, Hill AF. Delineating common molecular mechanisms in Alzheimer's and prion diseases [J]. Trends Biochem Sci.2006.31(8):465-72.
    [134]Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress:cross-talk and redox signalling [J]. Biochem J.2012.441(2):523-40.
    [135]Lovell MA, Markesbery WR. Oxidative damage in mild cognitive impairment and early Alzheimer's disease[J]. J Neurosci Res.2007.85(14):3036-40.
    [136]Resende R, Moreira PI, Proenca T, et al. Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease[J]. Free Radic Biol Med.2008.44(12):2051-7.
    [137]Candore G, Bulati M, Caruso C, et al. Inflammation, cytokines, immune response, apolipoprotein E, cholesterol, and oxidative stress in Alzheimer disease:therapeutic implications[J]. Rejuvenation Res.2010.13(2-3):301-13.
    [138]Cagnin A, Brooks DJ, Kennedy AM, et al. In-vivo measurement of activated microglia in dementia[J]. Lancet.2001.358(9280):461-7.
    [139]Innamorato NG, Lastres-Becker I, Cuadrado A. Role of microglial redox balance in modulation of neuroinflammation. Curr Opin Neurol [J].2009.22(3):308-14.
    [140]Li Y, Liu L, Barger SW, Griffin WS. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway [J]. J Neurosci.2003.23(5):1605-11.
    [141]Jimenez S, Baglietto-Vargas D, Caballero C, et al. Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease:age-dependent switch in the microglial phenotype from alternative to classic[J]. J Neurosci.2008.28(45): 11650-61.
    [142]Lacor PN, Buniel MC, Furlow PW, et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's diseasefJ]. J Neurosci.2007.27(4):796-807.
    [143]Deane R, Bell RD, Sagare A, Zlokovic BV. Clearance of amyloid-beta peptide across the blood-brain barrier:implication for therapies in Alzheimer's disease[J]. CNS Neurol Disord Drug Targets.2009.8(1):16-30.
    [144]Hellstrom-Lindahl E, Ravid R, Nordberg A. Age-dependent decline of neprilysin in Alzheimer's disease and normal brain:inverse correlation with A beta levels[J]. Neurobiol Aging.2008.29(2):210-21.
    [145]Carpenter TC, Stenmark KR. Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak[J]. Am J Physiol Lung Cell Mol Physiol.2001.281(4):L941-8.
    [146]Rockenstein E, Torrance M, Adame A, et al. Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation[J]. J Neurosci. 2007.27(8):1981-91.
    [147]Spencer B, Marr RA, Rockenstein E, et al. Long-term neprilysin gene transfer is associated with reduced levels of intracellular Abeta and behavioral improvement in APP transgenic mice[J]. BMC Neurosci.2008.9:109.
    [148]Madani R, Poirier R, Wolfer DP, et al. Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo[J]. J Neurosci Res.2006. 84(8):1871-8.
    [149]Yasojima K, Akiyama H, McGeer EG, McGeer PL. Reduced neprilysin in high plaque areas of Alzheimer brain:a possible relationship to deficient degradation of beta-amyloid peptide[J]. Neurosci Lett.2001.297(2):97-100.
    [150]Farris W, Schutz SG, Cirrito JR, et al. Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy[J]. Am J Pathol.2007.171(1):241-51.
    [151]Shen Y, Joachimiak A, Rosner MR, Tang WJ. Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism[J]. Nature.2006.443(7113):870-4.
    [152]Wang DS, Dickson DW, Malter JS. beta-Amyloid degradation and Alzheimer's disease[J]. Journal of biomedicine & biotechnology.2006.2006(3):58406.
    [153]Leissring MA, Farris W, Chang AY, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death[J]. Neuron.2003.40(6):1087-93.
    [154]Qiu WQ, Walsh DM, Ye Z, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation[J]. J Biol Chem.1998.273(49):32730-8.
    [155]Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo[J]. Proc Natl Acad Sci U S A.2003.100(7):4162-7.
    [156]Crossgrove JS, Li GJ, Zheng W. The choroid plexus removes beta-amyloid from brain cerebrospinal fluid[J]. Experimental biology and medicine (Maywood, N.J.).2005.230(10): 771-6.
    [157]Herz J, Strickland DK. LRP:a multifunctional scavenger and signaling receptor[J]. J Clin Invest.2001.108(6):779-84.
    [158]Cam JA, Bu G. Modulation of beta-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family[J]. Mol Neurodegener.2006.1:8.
    [159]Donahue JE, Flaherty SL, Johanson CE, et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease[J]. Acta Neuropathol.2006.112(4):405-15.
    [160]Shibata M, Yamada S, Kumar SR, et al. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier[J]. J Clin Invest.2000. 106(12):1489-99.
    [161]Zerbinatti CV, Wozniak DF, Cirrito J, et al. Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein[J]. Proc Natl Acad Sci U S A.2004.101(4):1075-80.
    [162]Deane R, Du Yan S, Submamaryan RK, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain[J]. Nat Med.2003.9(7): 907-13.
    [163]Stern D, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation endproducts:a multiligand receptor magnifying cell stress in diverse pathologic settings[J]. Adv Drug Deliv Rev.2002.54(12):1615-25.
    [164]Wang MY, Ross-Cisneros FN, Aggarwal D, Liang CY, Sadun AA. Receptor for advanced glycation end products is upregulated in optic neuropathy of Alzheimer's disease[J]. Acta Neuropathol.2009.118(3):381-9.
    [165]Zlokovic BV. Clearing amyloid through the blood-brain barrier[J]. J Neurochem.2004.89(4): 807-11.
    [166]Schmidt AM, Sahagan B, Nelson RB, Selmer J, Rothlein R, Bell JM. The role of RAGE in amyloid-beta peptide-mediated pathology in Alzheimer's disease[J]. Current opinion in investigational drugs (London, England:2000).2009.10(7):672-80.
    [167]Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF, Yan SD. RAGE:a potential target for Abeta-mediated cellular perturbation in Alzheimer's disease[J]. Curr Mol Med.2007.7(8): 735-42.
    [168]贾耿.督脉、足太阳、任脉、肾精实质试探[J].湖南中医学院学报.2000.(04):47-49.
    [169]胡俊霞,冯毅,王桂玲.王氏“老十针”对中风患者运动能力及日常生活能力的影响[J].中国中医药信息杂志.2013.(11):69-70.
    [170]张曦,王世娟,王恩龙.运用石学敏“醒脑开窍”针法治疗中风的研究[J].实用中医内科杂志.2012.(04):22-23.
    [171]高凌云,胡翔龙,许小洋,吴宝华,陈凌.督脉循行线下深部组织温度的检测[J].针刺研究.2006.(03):159-162.
    [172]许小洋,胡翔龙,吴宝华.督脉循行线下深部组织氧分压的实验观察[J].针刺研究.2002.(04):252-255.
    [173]Prediger RD, Franco JL, Pandolfo P, et al. Differential susceptibility following beta-amyloid peptide-(1-40) administration in C57BL/6 and Swiss albino mice:Evidence for a dissociation between cognitive deficits and the glutathione system response[J]. Behav Brain Res.2007. 177(2):205-13.
    [174]Gouras GK, Tampellini D, Takahashi RH, Capetillo-Zarate E. Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease[J]. Acta Neuropathol.2010. 119(5):523-41.
    [175]Malm T, Ort M, Tahtivaara L, et al. beta-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or beta-amyloid deposits[J]. Proc Natl Acad Sci U S A.2006.103(23):8852-7.
    [176]Wang D, Noda Y, Zhou Y, et al. The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid25-35 i.c.v.-injected mice:involvement of dopaminergic systems[J]. Neuropsychopharmacology. 2007.32(6):1261-71.
    [177]Medeiros R, Prediger RD, Passos GF, et al. Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer's disease:relevance for the behavioral and synaptic deficits induced by amyloid beta protein[J]. J Neurosci.2007.27(20):5394-404.
    [178]Watanabe T, Iwasaki K, Ishikane S, et al. Spatial memory impairment without apoptosis induced by the combination of beta-amyloid oligomers and cerebral ischemia is related to decreased acetylcholine release in rats[J]. J Pharmacol Sci.2008.106(1):84-91.
    [179]Ho SC, Liu JH, Wu RY. Establishment of the mimetic aging effect in mice caused by D-galactose[J]. Biogerontology.2003.4(1):15-8.
    [180]罗焕敏,陈子晟.一种新的老年痴呆动物模型[J].中国老年学杂志.2003.(03):179-182.
    [181]Xiao F, Li XG, Zhang XY, et al. Combined administration of D-galactose and aluminium induces Alzheimer-like lesions in brain[J]. Neurosci Bull.2011.27(3):143-55.
    [182]Takeda T, Hosokawa M, Takeshita S, et al. A new murine model of accelerated senescence[J]. Mech Ageing Dev.1981.17(2):183-94.
    [183]Kim BH, Meeker HC, Shin HY, et al. Physiological properties of astroglial cell lines derived from mice with high (SAMP8) and low (SAMR1, ICR) levels of endogenous retrovirus[J]. Retrovirology.2008.5:104.
    [184]Takeda T. [Senescence-accelerated mouse (SAM):with special reference to age-associated pathologies and their modulation]. Nihon eiseigaku zasshi. Japanese journal of hygiene[J]. 1996.51(2):569-78.
    [185]Spangler EL, Patel N, Speer D, et al. Passive avoidance and complex maze learning in the senescence accelerated mouse (SAM):age and strain comparisons of SAM P8 and R1[J]. J Gerontol A Biol Sci Med Sci.2002.57(2):B61-8.
    [186]Tomobe K, Nomura Y. Neurochemistry, neuropathology, and heredity in SAMP8:a mouse model of senescence[J]. Neurochem Res.2009.34(4):660-9.
    [187]Del VJ, Duran-Vilaregut J, Manich G, et al. Early amyloid accumulation in the hippocampus of SAMP8 mice[J]. J Alzheimers Dis.2010.19(4):1303-15.
    [188]Canudas AM, Gutierrez-Cuesta J, Rodriguez MI, et al. Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM). Mech Ageing Dev[J].2005. 126(12):1300-4.
    [189]Tomobe K, Okuma Y, Nomura Y. Impairment of CREB phosphorylation in the hippocampal CA1 region of the senescence-accelerated mouse (SAM) P8[J]. Brain Res.2007.1141: 214-7.
    [190]Wu B, Ueno M, Onodera M, et al. RAGE, LDL receptor, and LRP1 expression in the brains of SAMP8[J]. Neurosci Lett.2009.461(2):100-5.
    [191]Knobloch M, Mansuy IM. Dendritic spine loss and synaptic alterations in Alzheimer's disease[J]. Mol Neurobiol.2008.37(1):73-82.
    [192]Bales KR, Liu F, Wu S, et al. Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice[J]. J Neurosci.2009.29(21):6771-9.
    [193]Ray S, Howells C, Eaton ED, et al. Tg2576 cortical neurons that express human Ab are susceptible to extracellular Abeta-induced, K+ efflux dependent neurodegeneration[J]. PLoS One.2011.6(4):e19026.
    [194]Middei S, Roberto A, Berretta N, et al. Learning discloses abnormal structural and functional plasticity at hippocampal synapses in the APP23 mouse model of Alzheimer's disease[J]. Learning & memory (Cold Spring Harbor, N.Y.).2010.17(5):236-40.
    [195]Duyckaerts C, Potier MC, Delatour B. Alzheimer disease models and human neuropathology: similarities and differences [J]. Acta Neuropathol.2008.115(1):5-38.
    [196]Clinton LK, Billings LM, Green KN, et al. Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice[J]. Neurobiol Dis.2007.28(1):76-82.
    [197]Su D, Zhao Y, Xu H, et al. Isoflurane exposure during mid-adulthood attenuates age-related spatial memory impairment in APP/PS1 transgenic mice[J]. PLoS One.2012.7(11):e50172.
    [198]Zhang QL, Jia L, Jiao X, et al. APP/PS1 transgenic mice treated with aluminum:an update of Alzheimer's disease model[J]. Int J Immunopathol Pharmacol.2012.25(1):49-58.
    [199]Filali M, Lalonde R, Theriault P, Julien C, Calon F, Planel E. Cognitive and non-cognitive behaviors in the triple transgenic mouse model of Alzheimer's disease expressing mutated APP, PS1, and Mapt (3xTg-AD) [J]. Behav Brain Res.2012.234(2):334-42.
    [200]Callaway NL, Riha PD, Wrubel KM, McCollum D, Gonzalez-Lima F. Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats[J]. Neurosci Lett.2002.332(2):83-6.
    [201]李翀,吕艳,李谈.电针足三里干预快速老化痴呆鼠大脑APP及Ap蛋白表达的实验研究[J].中华中医药学刊.2010.(10):2221-2223.
    [202]薛卫国,张忠,许红,吴海霞,白丽敏.电针对淀粉样前体蛋白转基因小鼠海马微血管淀粉样沉积的影响及其与低密度脂蛋白相关受体1的关系[J].针刺研究.2011.(02):95-100.
    [203]薛卫国,张忠,白丽敏,许红,吴海霞.电针对β-淀粉样前体蛋白转基因小鼠行为学及 其淀粉样前体蛋白、p淀粉样蛋白及胆碱乙酰转移酶水平的影响[J].针刺研究.2009.(03):152-158.
    [204]朱晓冬,蒋希成,毛翔.针刺对D-半乳糖复制阿尔茨海默病模型大鼠脑组织中p-APP、Tau蛋白表达的影响[J].中医学报.2011.(08):954-955.
    [205]蒋希成,姜国华,于洋.针刺对老年性痴呆大鼠脑组织中tau蛋白表达的影响[J].针灸临床杂志.2008.(11):38-39.
    [206]毛翔,朱晓冬,蒋希成,张蕴.电针对阿尔茨海默病模型大鼠行为学的影响.上海针灸杂志[J].2012. (10):764-766.
    [207]望庐山,周丽莎.电针治疗对阿尔茨海默病大鼠Ach、ChAT、AchE的影响[J].针灸临床杂志.2009.(06):40-42+54.
    [208]张海燕,刘忠锦,廉洁,陈志伟.电针对阿尔茨海默病模型大鼠海马胆碱能神经元的影响[J].中国医药导报.2013.(13):11-13.
    [209]刘智斌,牛文民,杨晓航,牛晓梅,王渊.嗅三针对老年痴呆大鼠学习记忆功能及海马胆碱乙酰化酶、乙酰胆碱酯酶活性的影响[J].针刺研究.2009.(01):48-51.
    [210]杨晓航,刘智斌,牛文民,牛晓梅,王渊.“嗅三针”对阿尔茨海默病大鼠海马毒蕈碱型受体的影响[J].针刺研究.2011.(02):90-94.
    [211]石学敏,韩景献,李平等.针刺对老化痴呆鼠脑兴奋性氨基酸水平影响的实验研究[J].中国针灸.1998.(11):49-52+4.
    [212]张晓琳,刘智艳,刘娟等.电针对老年性痴呆大鼠记忆功能减退的影响[J].中华中医药杂志.2012.(03):706-709.
    [213]朱书秀,孙国杰.电针对阿尔茨海默病大鼠海马区胶质细胞活化及神经元超微结构的影响[J].中医杂志.2009.(06):522-525.
    [214]方剑乔,朱书秀,张英,王芳,朱青艳.电针对阿尔茨海默病模型大鼠额叶胶质细胞的影响[J].湖北中医杂志.2013.(02):26-27.
    [215]唐勇,余曙光,罗松,韩婷,尹海燕.电针对老年性痴呆大鼠胆碱能神经元损伤的保护作用[J].中西医结合学报.2006.(04):374-377.
    [216]Dunham JS, Deakin JF, Miyajima F, Payton A, Toro CT. Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains[J]. J Psychiatr Res.2009.43(14):1175-84.
    [217]Li XZ, Yan J, Huang SH, Zhao L, Wang J, Chen ZY. Identification of a key motif that determines the differential surface levels of RET and TrkB tyrosine kinase receptors and controls depolarization enhanced RET surface insertion[J]. J Biol Chem.2012.287(3): 1932-45.
    [218]马骏,王彦春,王述菊,程宇核,周冰,李娜.电针对阿尔茨海默病模型大鼠海马区神经营养因子及其受体表达的影响[J].针灸临床杂志.2010.(07):63-66.
    [219]周围,吕小笑.电项针疏、密波对AD模型大鼠空间记忆能力及海马区BDNF/TrkBmRNA的影响[J].针灸临床杂志.2013.(12):46-48.
    [220]刘智斌,牛文民,杨晓航,牛晓梅,王渊.“嗅三针”对阿尔茨海默病大鼠海马Bcl-2和 Bax表达的干预效应[J].针刺研究.2011.(01):7-11.
    [221]熊萍,杜艳军,夏微光,刘若兰,孙国杰.电针加艾灸对AD模型大鼠海马细胞周期调节因子cyclinD1、p16 INK4a的影响[J].湖北中医杂志.2012.(11):27-28.
    [222]夏微光,杜艳军,孙国杰,熊萍,刘若兰.电针加灸对AD模型大鼠细胞周期调节因子eyclinE、p21/cip的影响[J].中西医结合研究.2012.(06):306-9.
    [223]杜艳军,宋杰,周华,陈帮国,王述菊,孙国杰.艾灸预刺激对阿尔茨海默病大鼠Hsp70、Hsp90的影响[J].辽宁中医杂志.2013.(03):577-9.
    [224]罗磊,孙国杰,杜艳军.针灸对AD模型大鼠海马神经元线粒体能量代谢相关蛋白的影响[J].中国针灸.2013.(10):913-8.
    [225]孙国杰,罗磊,杜艳军,孔立红.针灸对AD模型大鼠海马神经元线粒体保护机制研究[J].中国针灸.2014.(02):157-62.
    [226]罗磊,杜艳军,孙国杰.针灸对阿尔茨海默病模型大鼠海马神经元线粒体中亲环蛋白D的影响[J].上海针灸杂志.2013.(12):1056-59.
    [227]方剑乔,朱书秀,张英,王芳,朱青艳.电针对阿尔茨海默病模型大鼠额叶与海马区磷酸化P38丝裂原活化蛋白激酶和白介素-1βmRNA的影响[J].针刺研究.2013.(01):35-39.
    [228]唐勇,余曙光,刘旭光,刘雨星.电针激活老年痴呆大鼠海马蛋白激酶信号通路的作用[J].中国临床康复.2005.(01):124-125.
    [229]易显富,彭力,张泽月等.电针对AP25-35致阿尔茨海默病模型大鼠CAMP/PKA/CREB信号转导通路的影响[J].中华实用诊断与治疗杂志.2014.(02):128-130.
    [230]Gray JR, Braver TS, Raichle ME. Integration of emotion and cognition in the lateral prefrontal cortex[J]. Proc Natl Acad Sci U S A.2002.99(6):4115-20.
    [231]Salimpoor VN, Benovoy M, Larcher K, Dagher A, Zatorre RJ. Anatomically distinct dopamine release during anticipation and experience of peak emotion to music[J]. Nat Neurosci.2011.14(2):257-62.
    [232]Evers S, Suhr B. Changes of the neurotransmitter serotonin but not of hormones during short time music perception[J]. Eur Arch Psychiatry Clin Neurosci.2000.250(3):144-7.
    [233]Smith A, Waters B, Jones H. Effects of prior exposure to office noise and music on aspects of working memory[J]. Noise Health.2010.12(49):235-43.
    [234]Purnell-Webb P, Speelman CP. Effects of music on memory for text[J]. Percept Mot Skills. 2008.106(3):927-57.
    [235]Simmons-Stern NR, Budson AE, Ally BA. Music as a memory enhancer in patients with Alzheimer's disease[J]. Neuropsychologia.2010.48(10):3164-7.
    [236]Corte B, Lodovici NP. [Music therapy on Parkinson disease] [J]. Ciencia & saude coletiva. 2009.14(6):2295-304.
    [237]Bernatzky G, Bernatzky P, Hesse HP, Staffen W, Ladurner G. Stimulating music increases motor coordination in patients afflicted with Morbus Parkinson[J]. Neurosci Lett.2004. 361(1-3):4-8.
    [238]Alladi PA, Roy T, Singh N, Wadhwa S. Prenatal auditory enrichment with species-specific calls and sitar music modulates expression of Bcl-2 and Bax to alter programmed cell death in developing chick auditory nuclei[J]. Int J Dev Neurosci.2005.23(4):363-73.
    [239]纪倩,梅旭晖,唐银杉,邓晓丰,赛音朝克图,李志刚.音乐电针和脉冲电针对慢性应激抑郁大鼠行为学和海马星形胶质细胞的影响[J].中华中医药杂志.2013.(03):648-651.
    [240]纪倩,李志刚,唐银杉,莫雨平,姚海江,赛音朝克图.不同电针刺激对慢性应激抑郁模型大鼠行为学及海马谷氨酸转运体的影响[J].针刺研究.2013.(03):202-7+219.
    [241]唐银杉,余仁锋,纪倩等.音乐电针对慢性应激抑郁模型大鼠海马单胺类神经递质表达的调节作用[J].北京中医药大学学报.2013.(04):263-7.
    [242]滕金艳,李志刚,白妍,赛音朝克图.不同电针对抑郁模型大鼠结肠黏膜脑肠肽GAS. NPY、CGRP含量的影响[J].世界中西医结合杂志.2013.(03):226-9.
    [243]滕金艳,李志刚,白妍,赛音朝克图.音乐电针对抑郁模型大鼠下丘脑和结肠黏膜β-内啡肽含量的影响[J].世界中西医结合杂志.2013.(04):348-50.
    [244]张淑丽,严晓燕,王素兰,王晓敏,刘利.音乐电针对脑出血大鼠脑组织及血清SOD和MDA的影响[J].针灸临床杂志.2011.(10):55-57.
    [245]张淑丽,王素兰,严晓燕,王晓敏,刘利.音乐电针对脑出血大鼠脑组织超微结构的保护作用[J].光明中医.2011.(10):2003-5.
    [246]东贵荣,东红升,裴浩.音乐电针对大鼠脑内CCKmRNA表达影响的对比研究[J].针灸临床杂志.2005.(03):58-60.
    [1]Verfaellie M, Keane MM. Preserved priming in auditory perceptual identification in Alzheimer's disease [J].Neuropsychologia 2000,38(12):1581-92.
    [2]Backman L, Small BJ. Stability of the preclinical episodic memory deficit in Alzheimer's disease [J]. Brain 2001,124(Pt 1):96-102.
    [3]Frick KM, Baxter MG, et al. Age-related spatial reference and working memory deficits assessed in the water maze [J]. Neurobiology of Aging,1995,6(2):149.
    [4]Wenk GL, Quack Q et al. No interaction of mematine with acelylcholine-sterase inhibitors approved for clinical use[J]. Life Sci,2000,66(12):1079-83.
    [5]Shoffner JM. Oxidative phosphorylation defects and Alzheimer's disease [J]. Neurogenetics.1997.1(1): 13-9.
    [6]Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo [J]. Nature.2002.416(6880):535-9.
    [7]Hampel H, Shen Y, Walsh DM, et al. Biological markers of amyloid beta-related mechanisms in Alzheimer's disease[J]. Exp Neurol.2010.223(2):334-46.
    [8]Hashimoto M, Rockenstein E, Crews L, Masliah E. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases [J]. Neuromolecular Med. 2003.4(1-2):21-36.
    [9]Li Y, Zhou W, Tong Y, et al. Control of APP processing and Abetageneration level by BACE1 enzymatic activity and transcription.Faseb[J],2006,20(2):285-92
    [10]Christensen M A, Zhou W, et al. Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase [J]. Mol Cell Biol,2004,24(2):865-74
    [11]Cho H J, Jin S M, Son S M, et al. Constitutive JAK2/STAT1activation regulates endogenous BACE1 expression in neurons[J].Biochem Biophys Res Commun,2009,386(1):175-80
    [12]Cho H J, Jin S M, Youn H D, et al. Disrupted intracellular calciumregulates BACE1 gene expression via nuclear factor of activated Tcells 1 (NFAT1)signaling[J]. Aging Cell,2008,7(2):137-47
    [13]Wen Y, Yu W H, Maloney B, et al. Transcriptional regulation ofbeta-secretase by p25/cdk5 leads to enhanced amyloidogenicprocessing [J]. Neuron,2008,57(5):680-90
    [14]Chen C H, Zhou W, et al. Increased NF-kappaB signallingup-regulates BACE1 expression and its therapeutic potential inAlzheimer's disease[J]. Int J Neuropsychopharmacol,2012,15(1):77-90
    [15]Qing H, Zhou W, Christensen M A, et al. Degradation of BACE by the ubiquitin-proteasome pathway[J]. Faseb J,2004,18 (13):1571-3
    [16]Tesco Q Koh Y H, Kang E L, et al. Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity [J]. Neuron,2007,54 (5):721-37
    [17]Miners JS, Baig S, Palmer J, Palmer LE, Kehoe PG, Love S. Abeta-degrading enzymes in Alzheimer's disease[J]. Brain pathology (Zurich, Switzerland),2008,18(2):240-52.
    [18]Shirotani K, Tsubuki S, Iwata N, etal. Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan and phosphoramidon sensitive endopeptidases [J] J Biol Chem,2001,276(24):21895-901.
    [19]Saido TC, Iwata N. Metabolism of amyloid beta peptide and pathogenesis of Alzheimer's disease. Towards presymptomatic diagnosis, prevention and therapy [J].Neurosci Res,2006,54(4):235-53.
    [20]Edbauer D,Will em M,Laminich S,et al. Insulin degrading enzyme rapidly removes the f3-amyloid precursor protein intracellular domain(AICD) [J]. JBiol Chem,2002,277 (16) 13389-93.
    [21]LixiaZhao,BrueeTeter, et al. Insulin-Degrading Enzyme as a Downstream Target of Insulin Receptor Signaling Cascade:Implieations for Alzheimer's Disease Intervention [J]. JNeurosei,2004,24 (49): 11120-6.
    [22]Kanemitsu H, Tomiyama T, Mori H. Human neprilysin is capableof degrading amyloid β peptide not only in the monomeric formbut also the pathological oligomeric form [J]. Neurosci Lett,2003,350(2): 113-6.
    [23]Sandoval K E, Farr S A, Banks W A, et al. Somatostatin receptorsubtype-4 agonist NNC 26-9100 decreases extracellular andintracellular Aβ(1-42)trimers [J]. Eur J Phamiacol,2012,683 (1-3):116-24.
    [24]Liang K, Yang L, Yin C, et al. Estrogen stimulates degradation ofbeta-amyloid peptide by up-regulating neprilysin [J]. J Biol Chem,2010,285(2):935-42.
    [25]Belyaev N D, Nalivaeva N N, Makova N Z, et al. Neprilysin geneexpression requires binding of the amyloid precursor proteinintracellular domain to its promoter:implications for Alzheimer'sdisease [J]. EMBO Rep,2009,10(1):94-100.
    [26]Bauer C, Pardossi-Piquard R, Dunys J, et al.γ-Secretase-mediated regulation of neprilysin:Influence of cell density and aging andmodulation by imatinib [J]. J Alzheimers Dis,2011,27(3):511-20.
    [27]Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration[J].Trends Neurosci, 2005,28(4):202-8.
    [28]Tamaki C, Ohtsuki S, Terasaki T. Insulin Facilitates the Hepatic Clearance of Plasma Amyloid (3-Peptide(1-40)by Intracellular Translocation of Low-Density Lipoprotein Receptor-Related Protein 1(LRP-1) to the Plasma Membrane in Hepatocytes [J].Mol Pharmacol,2007,72(4):850-5.
    [29]Gauthier A,Vassiliou G,Benoist F, et al. Adipocytelow density lipoprotein receptor-related protein gene ex-pression and function is regulated by peroxisome proliferator activated receptor gamma[J].The Journal of bio-logical chemistry,2003,278(14):11945-53.
    [30]Pichiule P, Chavez JC, et al. Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia[J]. Biol Chem.2007,282:36330-40.
    [31]Yao D,Brownlee M. Hyperglycemia-induced reactive oxygen species increaseexpression of the receptor for advanced glycation end products (RAGE) and RAGEligands[J]. Diabetes.2010;59(1):249-55.
    [32]Harja E,Bu DX, Hudson BI, Chang JS, Shen X,Hallam K, Kalea AZ, Lu Y,Rosario RH, Oruganti S, Nikolla Z, Belov D,Lalla E, Ramasamy R,Yan SF, Schmidt AM. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and itsligands in apoE-/- mice[J]. J Clin Invest.2008;118(1):183-94.

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