臺灣博碩士論文加值系統

近年來，由於社會、經濟及醫藥等各方面之進步，許多已開發國家已快速邁入「老年化社會」。老化是引起失智症最主要的危險因素，在台灣，65歲以上的老年人口失智症盛行率高達2.5~5%，因此國內日益重視老化及老年人疾病的研究。【本草綱目】及【全國中草藥】中記載龍眼具有治療健忘、神經衰弱、心悸及失眠之功效，其在台灣產量豐碩且價廉物美，因此本研究以龍眼為材料，利用95% 乙醇進行萃取，並以誘發學習障礙之藥物和併用水迷宮之模式，探討給予不同濃度之龍眼萃取物對大鼠學習記憶能力影響，實驗後犧牲動物，測其皮質及海馬迴中乙醯膽鹼酯酶活性、神經成長因子和硫氫化合物以及肝臟中超氧化物歧化酶、觸酶及麩胱甘肽含量，以探討其抗氧化損傷暨神經生化機制。本實驗分七組：(1)控制組(生理食鹽水) (2) Scopolamine (SCP) (3) Piracetam-SCP (4) 龍眼萃取物(LE-SCP) 1 g/kg餵食7天 (5) LE-SCP 2 g/kg餵食7天(6) LE-SCP 0.5 g/kg餵食14天 (7) LE-SCP 1 g /kg餵食14 天。結果發現SCP可造成水迷宮空間學習操作、參考記憶暨工作記憶再學習與再現等學習操作能力等障礙；龍眼萃取物可改善因SCP所誘發之水迷宮學習操作、參考記憶與工作記憶障礙，其中更以餵食龍眼萃取物1 g/kg連續14天之改善效果最顯著，而正對照藥物Piracetam亦具改善作用。本實驗發現SCP
可造成皮質層及海馬迴神經成長因子、SH化合物的含量降低、乙醯膽鹼酯酶含量升高，以及肝臟中SOD、GSH-Px、Catalase活性下降。龍眼粗萃物則可改善SCP所誘導之現象，包括提高皮質層及海馬迴神經成長因子和SH化合物的含量、降低乙醯膽鹼酯酶之活性，以及提升肝臟中SOD、GSH-Px、Catalase活性，和正對照藥物Piracetam作用類似。因此可顯示出龍眼粗萃物確具增進大鼠水迷宮空間記憶之能力，不論ㄧ週或兩週連續給藥下皆可改善SCP誘發學習障礙之作用。

Many developed countries have fast stepped into aging population society because of the progress of society, economy and medicine. Aging is a significant risk factor for dementia. The ratio of population above 65 year old suffering from dementia reaches as high as 2.5~5% in Taiwan. Longan has been recorded to have the effect of remedying forgetfulness, neurasthenia, palpitation and insomnia in books of ‘Native Chinese Plants’ and ’National Chinese Medicine’. The output of longan is plentiful as well as the low-price in Taiwan during the summer season. The objective of this research is to investigate the ameliorating effects of the ethanol extract of longan on drug induced memory impairment in rat. The Morris water-maze was used for evaluating learning and memory ability. After the experiment, rats were sacrificed and their acethylcholinesterase (AChE) activity, nerve growth factor (NGF), superoxide dimustase (SOD)and glutathione peroxidase (GSH-Px) levels in rat cortex, hippocampus and were evaluated seven groups including normal control (0.9% saline), scopolamine (SCP), piracetam-SCP, longan extract feeding after SCP treatment of 1 g /kg for 7 days, 2 g /kg for 7
days, 0.5g /kg for 14 days and 1g /kg for 14days of rats were used in this study. SCP was used to induce water maze spatial performance and deficits in reference and working memory. Longan extracts and positive control (piracetam) attenuated the performance impairment and memory deficit in reference and working memory, while the improving effect of LE-SCP 1g /kg for 14day was mostly significant than other group. In this study, we found in the SCP-induced rats had lower NGF and total thiol and higher AChE in cortex and hippocampus, and lower SOD, GSH-Px, CAT and total thiol in liver. Longan extract repaired the SCP induced performance impairment and memory deficits in rats through its antioxidant, proliferation of NGF, and inhibition of AChE activity. The SCP-induced impairment of water maze spatial performance could be improved in rats fed with longan extract for 1 week or 2 weeks consecutively.

中文摘要 I
Abstract III
誌謝 V
目錄 VI
圖表目錄 X
第1章 前言 1
第2章 文獻回顧 3
2.1 自由基與老化 3
2.1.1 自由基老化理論(Free radical theory of aging) 3
2.1.2 自由基與活性氧對生物體之影響 6
2.1.3 氧化壓力與疾病相關性之探討 6
2.2 老年失智症之介紹 8
2.2.1 阿茲海默症(Alzheimer’s Dusease) 13
2.2.2 阿茲海默症之成因 13
2.2.3 阿茲海默症的臨床症狀 17
2.2.4 阿茲海默症之治療 20
2.3 學習記憶考察 25
2.3.1 學習記憶之形成程……………………………...…………..25
2.3.2 學習記憶實驗模型 26
2.3.2.1 巴甫洛夫條件反應( Pavlovian conditional reflex) 26
2.3.2.2 操作性條件反射(operative conditional reflex) 29
2.3.2.3 逃避或迴避性條件反射(escape or avoidance conditional reflex) 29
2.3.2.4 辨別性學習(discrimination training) 30
2.4 龍眼之介紹………………………………………………………..31
2.4.1 龍眼在植物學上的分類位置 31
2.4.2 龍眼屬植物之共同特徵 31
2.4.3 植物形態 32
2.4.4 分佈及採製 32
2.4.5 藥材 32
2.4.6 性味功能 32
2.4.7 功效 34
2.4.8 化學成分 34
2.4.9 龍眼之應用與生理活性 34
2.4.9.1 滋補強壯作用 34
2.4.9.2 抑菌作用 35
2.4.9.3 抗氧化作用 35
2.4.9.4 抗刺激作用 35
2.4.9.5 增強免疫作用 35
2.4.9.6 內分泌之改善作用 36
2.4.9.7 抗衰老作用 36
第3章 材料與方法 37
3.1 實驗設計 37
3.2 實驗材料 37
3.3 實驗動物 39
3.4 儀器設備 39
3.5 藥品試劑 39
3.6 龍眼粗萃取物之製備 40
3.7 龍眼粗萃取物之成分分析 40
3.7.1 粗蛋白之測定 40
3.7.2 粗脂肪之測定 40
3.7.3 粗纖維之測定 41
3.7.4 水分之測定 41
3.7.5 灰分之測定 41
3.7.6 碳水化合物之測定 41
3.8 活動量測試(open field test activity) 42
3.9 Morris水迷宮實驗(Morris water maze) 42
3.10 組織器官之處理 46
3.11 總蛋白質含量之測定 46
3.12 乙醯膽鹼酯酶(acetylcholinesterase, AChE)活性測定 46
3.12.1 組織均質液之製備 46
3.12.2 組織均質液AChE活性測定 46
3.13 神經成長因子(Nerve growth factor, NGF) 含量之測定 47
3.13.1 樣品製備 47
3.13.2 NGF之定量 47
3.14 組織抗氧化分析 48
3.14.1 超氧化歧化酶(superoxide dismutase) 48
3.14.1.1 組織均質液之製備 48
3.14.1.2 組織均質液SOD活性測定 48
3.14.2 麩胱甘肽過氧化酶(glutathione peroxidase)之分析 49
3.14.2.1 組織均質液之製備 49
3.14.2.2 組織均質液GSH-Px活性測定 49
3.14.3 觸酶(catalase)活性之分析 49
3.14.3.1 組織均質液之製備 49
3.14.3.2 組織均質液CAT活性測定 49
3.14.4 總含硫化合物(total thiol)濃度測定 50
3.14.4.1 組織均質液之製備 50
3.14.4.2 組織均質液total thiol濃度測定 50
3.15 統計分析 51
第4章 結果與討論 52
4.1 龍眼粗萃物之製備與成分分析 52
4.1.1 龍眼萃取物之萃取率 52
4.1.2 龍眼粗萃物之一般成分分析 52
4.2 動物實驗之大鼠體重變化 52
4.3 大鼠活動量試驗 56
4.4 Morris水迷宮實驗 56
4.4.1 龍眼萃取物對SCP誘發記憶障礙大鼠水迷宮空間性 學習操作障礙之影響 56
4.4.2 龍眼萃取物對SCP誘發記憶障礙大鼠水迷宮參考記 憶障礙之影響 58
4.4.3 龍眼萃取物對SCP誘發記憶障礙大鼠水迷宮非空間 性游泳操作能力障礙之影響 58
4.3.4 龍眼萃取物對SCP誘發記憶障礙大鼠水迷宮工作記 憶障礙之影響 62
4.4 器官重量 66
4.5 總蛋白質含量之測定 66
4.6 乙醯膽鹼酯酶(acetylcholinesterase, AChE)活性測定 66
4.7 神經成長因子(NGF) 含量之測定 71
4.8 組織抗氧化分析 76
4.8.1 超氧化物歧化酶(superoxide dismutase；SOD)活性測 定 76
4.8.2 麩胱甘肽過氧化酶(glutathione peroxidase；GSH-Px) 之分析 76
4.8.3 觸酶(catalase, CAT)活性測定 79
4.8.4 總含硫化合物(total thiol)濃度測定 79
第5章 結論 87
參考文獻 89
作者簡介 103

王克先。1995。學習心理學。桂冠圖書股份有限公司。臺北，台灣。
王詩儀。2004。槐花萃取物對老化促進小鼠體內抗氧化作用及生理效應 之研究。靜宜大學食品營養學系研究所碩士論文。
王慧琴、白潔塵、蔣保李、馬忠傑、劉麗娟、付希娟、沈家芹、張宏佛、信東、王興翠。1994。龍眼肉提取液抗自由基及免疫增強作用的實驗研究。中國老年學雜誌 14(4)：227-9。
王文科、王智弘譯。2002。學習心理學—學習心理導論。五南圖書出版股份有限公司。臺北，台灣。
內政部。2006。人口統計資料。行政院。2007年1月3日，取自：http://www.moi.gov.tw/
杜易潔。2001。白术萃取物對老化促進小白鼠學習記憶能力之影響。靜宜大學應用化學研究所碩士論文。
李雪華、龍聖京、謝雲峰、韋巍。2004。龍眼多醣、荔枝多醣的分離提取物及其抗氧化作用的探討。廣西醫科大學學報 21(3)：342-4。
阮迪云、奉天德。1996。神經生理學。中國科技大學。北京市。
林國華。1987。常見中草藥(第四冊)。好兄弟出版社。台北市。台灣。
邱逸榛、何玉婷、陳婉庭、徐亞瑛。2004。簡介阿茲海默氏症與其照護。長期照護雜誌 7(4): 289-304.
吳華慧、李雪華、邱莉。2004。 荔枝、龍眼果肉及荔枝、龍眼多醣清除活性氧自由基的研究。食品科學 25(5)：166-9。
許蘭芝、王洪崗、耿秀芳、冷萍。2002。龍眼肉乙醇提取物對雌性大鼠垂體—性腺軸的作用。中醫葯信息 19(5)：57-8。
陳華智。1999。龍眼成分研究。中國醫藥學院中國藥學研究所碩士論文。
葉宗勳。國際厚生健康園區。2006年8月26日，取自：http://www.24drs.com/special_report/Alzheimers_disease
農興旭、李茂。1989。桂圓肉和蛤蚧提取液的藥理作用。中國中藥雜誌 14(6)：45-7。
農業委員會。2006。龍眼產量統計。行政院。2006年10月7日，取自：http://www.coa.gov.tw/
劉宣良、陳錦文、林近中、蘇永成、吳宜靜。2005。人腦的神祕訪客—阿茲海默氏症。科學發展 389：70-3。
蔡汎修。2001。阿魏酸對Amyloid β-peptide-(1-40)誘發大鼠學習 障礙改善作用機制。中國醫藥學院中國藥學研究所碩士論文。
鄭頌仁。1999。六味地黃丸改善大鼠學習障礙之研究。中國醫藥學院中國藥學研究所碩士論文。
蕭培根、連文琰。1998。原色中藥原植物圖鑑(上冊)。南天書局有限公司。台灣。
錢曾年、顧振綸、金黎清、謝梅林、陳葆荃。1992。吡拉西坦對大鼠腦Na+-K+-ATP酶、單胺氧化酶的影響及其抗氧化作用。中國藥理學報 13(1): 48-50。
謝佳玲。2002。蛇床子及其活性成分對於大鼠改善學習記憶障礙作用之研究。中國醫藥學院中國藥學研究所碩士論文。
謝明村、邱年永、謝文全、張賢哲、林景彬、廖江川、林文川、陳忠川、陳欽銘。1988。中國藥材學。正中書局有限公司。臺北，台灣。
Access Economics Inc.。2005。失智症亞太地區盛行報告。1-9。
Aebi HE. 1983. Catalase. In “Methods of Enzymatic Analysis”. v.3 pp. 273-86.
Alfin International. Retrieved March 12, 2006, from the Word Wide Web: http: //alfin2100.blogspot.com/
Andrew AG, Howland DS, Trusko SP, Savage MJ, Lang DM, Greenberg BD, Siman R, Scott RW. 1996. Enhanced amyloidogenic processing of the β-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer’s disease mutations and a humanized Aβ sequence. The journal of biological chemistry 271(38): 23380-8.
AOAC. 1984. Official method of analysis. 14th ed. Association of official analytical chemists. Washington D.C. USA.
AOAC. 1995. Official method of analysis. 15 th ed. Association of official analytical chemists. Washington D.C. USA.
Arvin B, Neville LF, Barone FC, Feuerstein GZ. 1996. The Role of Inflammation and Cytokines in Brain Injury. Neuroscience and biobehavioral reviews 20(3): 445-52.
Ashok BT, Ali R. 1999. The aging paradox: free radical theory of aging. Experimental gerontology 34: 293-303.
Bancher C, Leitner H, Jellinger K, Eder H, Setinek U, Fischer P, Wegiel J, Wisniewski HM. 1996. On the relationship between measles virus and Alzheimer neurofibrillary tangles in subacute sclerosing panencephalitis. Neurobiology of aging 17(4): 527-33.
Blass JP. Brain metabolism and brain disease: Is metabolic deficiency the proximate cause of Alzheimer dementia? Journal of neuroscience research 66(5): 851-6.
Blum J, Fridovich I. 1985. Inactivation of glutathione peroxidase by superoxide radical. Archives of biochemistry and biophysics 240(2): 500-8.
Braak H, Braak E. 1991. Neuropathological stageing of Alzheimer-related changes. Acta neuropathol 82: 239-59.
Braak H, Braak E, Bohl J, Bratzke H. 1998. Evolution of Alzheimer’s disease related cortical lesions. Journal of neural transmission supplementum 54: 97-106.
Bradford MM. 1976. A rapid and sensitive method for the quanitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical biochemistry 72: 248-54.
Breitner JCS. 1996. Inflammatory processes and antiinflammatory drugs in Alzheimer's disease: A current appraisal. Neurobiology of aging 17(5): 789-94.
Butterfield DA, Drake J, Pocernich C, Castegna A. 2001. Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid β-peptide. TRENDS in molecular medicine 7 (12): 548-54.
Chan YC, Wang MF, Chang HC. 2003. Polygonum multiflorum extracts improve cognitive performance in senescence accelerated mice. The American journal of Chinese medicine 31(2): 171-9.
Chen TH, Huang HP, Mastsumoto Y, Wu SH, Wang MF, Chung SY, Uezu K, Moriyama T, Uezu E, Korin T, Sato S, Yamamoto S. 1996. Effects of dietary nucleoside-nucleotide mixture on memory in aged and young memory deficient mize. Life sciences 59(21): 325-30.
Conway EL. 1998. Brain lesions and delayed water maze learning deficits after intracere- broventricular spermine. Brain research 800(1): 10-20.
Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, McCord JM, Harman D. Oxygen radicals and human disease. Annals of internal medicine 107(4): 526-45.
Decker MW, McGaugh JL. 1991. The role of interactions between the cholinergic system and other neuromodulatory systems in learing and memory. Synapse7(2): 151-68.
Demirovic J, Prineas P, Loewenstein D, Bean J, Duara R, Sevush S, Szapocznik J. 2003. Prevalence of dementia in three ethnic groups: the south Florida program on aging and heath. Annals of epidemiology 13(6): 472-8.
Diez-Ariza M, Redonodo C, Garca-Alloza M, Lasheras B, Rio JD, Ramirez MJ. 2003. Flumazenil and tacrine increase the effectiveness of ondansetron on scopolamine-induced impairment of spatial learning in rats. Psychopharmacology 169: 35-41.
East Tennessee State University. Retrieved March 2, 2006, from the Word Wide Web: http://faculty.etsu.edu/currie/images/muscle
Egashira N, Yuzurihara M, Hattori N, Sakakibara I, Ishige A. 2003. Ninjin-yoei-to (Ren-Shen-Yang-Rong-Tang) and Polygalae radix improves scopolamine-induced impairment of passive avoidance response in mice. Phytomedicine 10: 467-3.
Ellie Crystal’s Metaphysical and Science. Retrieved Apirl 14, 2007, from the Word Wide Web: http://www.crystalinks.com/alzheimers.html
Ellman GL. 1959. Tissue sulfhydryl groups. Archives of biochemistry and biophysics 82: 70-7.
Ellman GL, Courteny D, Andres V, Featherstone RM. 1961. A new and rapid colorimetric of acetylcholinesterase activity. Biochemcial pharmacology 7: 88-95.
El-Sherbiny DA, Khalifa AE, Attia AS, Eldenshary EEDS. 2003. Hypericum pergoratum extract demonstrates antioxidant properties against elevated rat brain oxidative status induced by amnestic dose of scopolamine. Pharmacology biochemistry and behavior 76: 525-33.
Faden AI. 1992. Dynorphin increases extracellular levels of excitatory amino acids in the brain through a non-opioid mechanism. The journal of neuroscience 12(2): 425-9.
Fan Y, Hu J, Li J, Yang Z, Xin X, Wang J, Ding J, Geng M. 2005. Effect of acidic oligosaccharide sugar chain on scopolamine-induced memory impairment in rats and its related mechanisms. Neuroscience letters 374: 222-6.
Fridovich. 1972. Superoxide radical and superoxide dismutase. Accounts of chemical research 5(10): 321.
Gautrin D, Gauthier S. 1989. Alzheimer's disease: environmental factors and etiologic hypotheses. The Canadian journal of neurological sciences 16(4): 375-87.
Gearhart DA, Middlemore ML, Terry AV. 2006. Journal of neuroscience methods 150: 159-73.
Giaconibi E. 1998. Aging, Alzheimer’s disease, and estrogen therapy. Experimental gerontology 33: 865-69.
Glenne GG, Wong CW. 1984. Alzheimer’s disease: intial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical and biophysical research communications 120(3): 885-90.
Glowonski J, Iversen LL. 1966a. Reglonal studies of catecholamines in the rat brain-Ι. Journal of neurochemistry 13: 655-69.
Glowonski J, Iversen LL . 1966b. Reglonal studies of catecholamines in the rat brain-Ⅲ: subcellullar distribution of endogenous and exogenous catecholamines in various brain regions. Biochemical pharmacology 15: 977-87.
Gouliaev AH, Senning A. 1994. Piracetam and other structurally related nootropics. Brain research reviews 19(2): 180-222.
Grundman M. 2000. Vitamin E and Alzheimer disease: the basis for additional clinical trials. The American journal of clinical nutrition 71: 603-6.
Gudasheva TA, Konstantinopol'skii MA, Ostrovskaya RU, Seredenin SB. 2001. Anxiolytic activity of endogenous nootropic dipeptide cyclo- prolylglycine in elevated plus-maze test. Bulletin of experimental biology and medicine 131(5): 464-6.
Halliwell B.1987. Oxygen radicals and metal ions: potential antioxidant intervention strategies. Annals of internal medicine 107: 526-45.
Hellweg R, Fischer W, Hock C, Gage FH, Björklund A, Thoenen H. 1990. Nerve gowth factor levels and choline acetyltransferase activity in the brain of aged rats with spatial memory itnpaimtents. Brain research 537(12): 123-30
Hernandez CM, Terry AV. 2005. Repeated nicotine exposure in rats: effects on memory function, cholinergic markers and nerve growth factor. Neuroscience 130: 997-1012.
Hu Y, Xia Z, Sun Q, Orsi A, Rees D. 2005. A new approach to the pharmacological regulation of memory: Sarasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain research 1060: 26-39.
Janas AM, CunninghamSC, Duffy KB, Devan BD, Greig NH, Holloway HW, Yu OS, Markowska AL, Ingram DK, Spangler EL. 2005. The cholinesterase inhibitor, phenserine, improves Morris watermaze performance of scopolamine-treated rats. Life sciences 76: 1073-81.
Jones KR, Black MJ, Oorschot DE. 1998. Do aluminium and/or glutamate induce alzheimer PHF-like formation? an electron microscopic study. Journal of neurocytology 27(1): 59-68.
Joshi H, Parle M. 2006. Brahmi rasayana improves learning and memory in mice. Advance access publication 3(1): 79-85.
Ju TC, Chen SD, Liu CC, Yang DI. 2005. Protective effects of S-nitrosoglutathione against amyloid ÎÎ-peptide neurotoxicity. Free radical biology and medicine 38(7): 938-49
Kang SY, Lee KY, Koo KJ, Yoon JS, Lim SW, Kim YC, Sung SH. 2005. ESP-102, a standardized combined extract of Angelica gigas, Saururus chinensis and Schinensis chinensis, significantly improved scopolamine -induced memory impairment in mice. Life sciences 76: 1691-705.
Kang SY, Lee KY, Park MJ, Kim YC, Markelonis GJ, Oh TH, Kim YC. 2003. Decursin from Angelica gigas mitigates amnesia induced by scopolamine in mice. Neurobiology of learning and memory 79: 11-8.
Kang SY, Lee KY, Sung SH, Park MJ, Kim YC. 2001. Coumarins isolated from Angelica gigas inhibit Acetylcholinesterase: Structure-Activity Relationships. Journal of natural products 64: 683-5.
Karlawish J. 2006. Alzheimer’s disease-clinical trials and the logic of clinical purpose. The new england journal of medicine 355(15): 1604-6.
Kopke E, Tung YC, Shaikh S, Alonso AC, Iqbal K and Grundke-Iqbal I. 1993. Microtubule-associated protein tau: abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. The Journal of biological chemistry 268(32): 24374-84.
Lee KY, Jeong EJ, Lee HS, Kim YC. 2006. Acteoside of Callicarpa dichotoma attenuates scopolamine-induced memory impairments. Biological pharmaceutical bulletin 29(1): 71-4.
Lefer DJ, Granger ND. 2000. Oxidative stress and cardiac disease. The American journal of medicine 109(4): 315-23.
Lin RT, Lai CL, Tai CT, Liu CK, Yen YY, Howng SL. 1998. Precalence and subtypes of dementia on southern Taiwan: Impact of age, sex, eduction, and urbanization. Journal of the neurological sciences 160: 67-75.
Marklund S, Marklund G. 1974. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. European journal of biochemistry 47: 469-74.
Martinez-Serrano A, Fischer W, Soderstron S, Ebendal T, Bjorklund A. 1996. Long-term functional recovery from age-induced spatial memory impairments by nerve growth factor gene transfer to the rat basal forebrain. Proceedings of the national academy of sciences of the united states of america 93(25): 6355-60.
Marx F, Blasko I, Pavelka M, Grubeck-Loebenstein B. 1998. The possible role of the immune system in Alzheimer’s disease. Experimental gerontology 33: 871-81.
Mattson MP. 2004. Pathways towards and away from Alzheimer's disease. Nature 430(7000): 631-9.
Meagher MW, Illich PA and Salinas JA. 1998. Physostigmine's impact on brief shock-induced Hypoalgesia Parallels its effect on memory. Neurobiology of learning and memory 70(3): 374-87.
Moreira PI, Smith MA, Zhu X, Honda K, Lee HG, Aliev G, Perry G. 2005. Oxidative damage and Alzheimer，s disease: are antioxidant therapies useful? Drug news& perspectives 18: 13-9.
Morishima-Kawashima M , Hasegawa M, Takio K, Suzuki M , Yoshida H , Titani K, Ihara Y. 1995. Proline-directed and non-proline-directed phosphorylation of PHF-tau. The American Society for biochemistry and molecular biology 170(13): 823-9.
Morris R. 1984. Developments of a water-maze procedure for studying spatial learning in the rat. Journal of neuroscience methods 11(1): 47-60.
Morrison-Bogorad M, Phelps C, Buckholtz N. 1997. Alzheimer disease research comes of age. The journal of the Americann medical association 277(10): 837-40.
Newmam SC. 1999. The precalence of depression in Alzheimer’s disease and vascular dementia in a population sample. Journal of affective disorders 52: 169-76.
Nishiyama N, Moriguchi T, Saito H. 1997. Beneficial effects of aged garlic extract on learning and memory impairment in the senescence-allelerated mouse. Experimental gerontology 32: 149-60.
Paglia DE, Valentine WN. 1967. Studies on the qualitative characterization of erythrocyte glutathione peroxidase. The Journal of laboratory and clinical medicine 70: 159-69.
Perick-Vance MA, Johnson CC, Rimmler JB. 1996. Alzheimer disease and apolipoprotein e-4 allele in an amish population. Annals of neurology 39(6): 700-4.
Pollard HB, Arispe N, Rojas E. 1995. Ion channel hypothesis for Alzheimer amyloid peptide neurotoxicity. Cellular and molecular neurobiology 15(5): 513-26.
Quartley B, EsselmontG, Taylor A, Dobrota M. 1993. Effect of oral aluminium citrate on short-term tissue distribution of aluminium. Food and chemical toxicology 31(8): 543-8.
Reilly RCO. 2006. Making working memory work: A computational model of learning in the Prefrontal Cortex and Basal Ganglia. Neural computation 18: 283-328.
Renvoize EB, Awad LO, Hambling MH. 1987. A sero-epidemiological study of conventionl infectious agents in Alzheimer’s disease. Age and aging 16: 311-20.
Ronner S,Yu J, Pizzo D, Werrbach-Perez K, Schliebs R Bigl V Perez-Polo JR. 1996. Effects of intraventricular transplantation of NGF-secreting cells on cholinergic basal forebrain neurons after partial immunolesion. Journal of neuroscience research 45(1): 45-56.
Roses AD. 1995. On the metabolism of apolipoprotein E and the Alzheimer diseases. Experimental neurology 132: 149-52.
Rubinszten DC. 1997. The cenetics of Alzheimer’s disease. Progress in neurobiology 52: 447-54.
Rylett RJ, Goddard S, Schmidt BM, Williams LR. 1993. Acetylcholine synthesis and release following continuous intracerebral administration of NGF in adult and aged Fischer-344 rats. The journal of neuroscience 13(9): 3944-55.
Semsei I. 2000. On the nature of aging. Mechanisms of aging and decelopment 117: 93-108.
Shimizu N, Kobayashi K, Hayashi K. 1984. The reaction of superoxide radical with catalase. Mechanism of the inhibition of catalase by superoxide radical. The Journal of biological chemistry 259(7): 4414-8.
Sohal RS. 2001. Oxidative stress hypothesis of aging. Free radical biology & medicine 33(5): 573-4.
Srivastava PK, Kayastha AM. 2000. Significance of sulfhydryl groups in the activity of urease from pigeonpea (Cajanus cajan L.)seeds. Plant science 159: 149-58.
Strittmatter WJ, Weisgraber KH, Goedert M, Saunders AM, D, Huang D, Corder HE, Dong LM, Jakes R, Alberts MJ, Gilbert JR. 1994. Hypothesis: microtubule instability and paired helical filament formation in the alzheimer disease brain are related to apolipoprotein E genotype. Experimental neurology 125(2): 163-71
Strittmatter WJ, Sanders AM, Schemchel D. 1993. Apolipoprotein E: high-avidity binding to ß-Amyloid and increased frequency of type 4 allele in late-onset familial alzheimer Disease. Proceedings of the national academy of sciences of the united states of America 90(5): 1977-81.
Tian Q, Lin ZQ, Wang XC, Chen J, Wang Q, Gong CX, Wang JZ. 2004. Injection of okadaic acid into the meynert nucleus basalis of rat brain induces decreased acetylcholine level and spatial memory deficit. Neuroscience 126: 277-84.
Trune DR, Hertler CK, Haun DKZ, and Sauter RW. 1990. Histochemistry of otic capsule sclerotic lesions in palmerston north autoimmune strain mice. Hearing research 48(3): 241-6.
Varadarajan S, Yatin S, Aksenov M, Butterfield A. 2000. Review: Alzheimer’s amyloid β-peptide-associated free radical oxidative stress and neuro- toxicity. Journal of structural biology 130: 184-208.
Wang MF, Chan YC, Wu CL, Wong YC, Hosoda K, Yamamoto S. 2004. Effects of Ganoderma on aging and learning memory ability in senescence accelerated mice. International congress series 1260: 399-404.
Wang JZ, Grundke-Iqbal I, Iqbal K. 1996. Glycosylation of microtubule -associated protein tau: an abnormal posttranslational modification in Alzheimer disease. Nature medicine 2(8): 871-5.
Wei X, Zhang Y, Zhou J. 1999. Alzheimer’s disease-related gene expression in the brain of senescence accelerated mouse. Neuroscience letters 268(3): 139-142.
Wickens AP. 2001. Ageing and the free radical theory. Respiration physiology 128: 379-91.
Yagi H, Katoh S, Akiguchi I, Takeda T. 1988. Age-related deterioration of ability of acquisition in memory and learning in senescence accelerated mouse: SAM-P/8 as an animal model of disturbances in recent memory. Brain research 474(1): 86-93.
Yamada N, Hattori A, Hayashi T, Nishikawa, Fukuda H, Fujino T. 2004. Improvement of scopolamine-induced memory by Z-ajoene in the water maze in mice. Pharmacology biochemistry and behavior 78: 787-91.
Yamada K, Tanaka T, Han D, Senzaki K, Kameyama T, Nabeshima T. 1999. Protective effects of idebenone and α-tocopherol on β-amyloid-(1-42) -induced learning and memory deficits in rats: implication of oxidative stress in β-amyloid-induced neurotoxicity in vivo. European journal of neuroscience 11: 83-90.
Yan JJ, Cho JY, Kim HS, Kim KL, Jung JS, Huh SO, Suh HW, Kim YH, Song DK. 2001. Protection against beta-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. British Journal of pharmacology 133(1): 89-96.
Zettler C, Christine D, Bridges M, Zhou XF, Rush RA. 1996. Detection of increased tissue concentrations of nerve growth factor with an improved extraction procedure. Journal of neuroscience research 46: 581-94.
Zingg JM, Ricciarelli R, Azzi A. 2000. Scavenger receptors and modified lipoproteins: fatal attractions? IUBMB life 49(5): 397-403.