星形胶质细胞在卵巢摘除结合注射D-半乳糖大鼠复合AD模型中的病理改变与功能障碍
摘要
目的:1.通过OVX结合注射D-gal建立复合因素AD动物模型,阐明雌激素剥夺和氧化应激在AD发生发展中的协同作用;2.研究与探索星形胶质细胞参与此AD模型的发病过程及机制。
方法:1.3月龄雌性SD大鼠,随机分为对照组(C)、OVX结合注射D-gal模型组(O+D)、单纯OVX组(O)、单纯注射D-gal组(D)和17-β雌二醇替代治疗组(O+D+E),6周后进行行为学测定、基底前脑胆碱能神经元ChAT免疫组化染色、海马区Aβ免疫组化染色、海马及皮质电镜超微结构观察和脂褐素与突触的定量分析来验证此模型。2.应用此模型(O+D),以2周和6周为观察时间点,通过海马区GFAP的免疫组化染色和western-blotting检测、GSH的生化检测、AChE组织化学染色与光密度分析及AChE活性测定、突触和血-脑屏障周围超微结构观察以及HRP通透性实验来研究星形胶质细胞在此模型中的病理改变与功能障碍。
结果:1.与C组相比,O+D组、O+D+E组、D组、O组均出现不同程度的行为学和病理学损害,以O+D组损害最为明显,具体表现为:(1)开场实验中,穿越格数明显减少;Y型迷宫达到学会标准的测试次数增多;跳台实验中,错误次数增加、潜伏期缩短。(2)在MS、NDB区域的ChAT免疫阳性胆碱能神经元明显减少,染色变浅,突起变短。(3)在海马的齿状回、CA1和下托观察到了其他组没有出现的细胞内Aβ沉积。(4)超微结构损害:细胞核变形扭曲;核内染色质聚集成不规则的高电子密度的块状;核膜破裂、不完整;胞浆内含有大量脂褐素、次级溶酶体;线粒体出现肿胀扭曲、变形,嵴断裂、空泡样变;细胞质内出现类似NFT改变;大量变性的突触结构。脂褐素数量明显增加,突触数量明显减少。2.(1)与C组和2w O+D组相比,6w O+D组大鼠在水迷宫行为学实验中,到达平台的潜伏期明显延长;穿越平台次数和在目标象限时间明显减少,而C组与2wO+D组大鼠之间没有统计学差异。(2)与C组和2w O+D组大鼠相比,6w O+D组大鼠在海马区出现了明显的胆碱能纤维终末的密度下降与AChE活性降低,而C组与2w O+D组大鼠之间没有统计学差异。(3)与C组相比,2w与6w O+D组大鼠海马区GFAP水平明显增加,但两组间没有统计学差异。(4)与C组和2w O+D组相比,6w O+D组出现了明显的GSH水平的降低。而2w O+D组则观察到了GSH水平的轻度升高,但与C组相比并没有明显的差异。(5)在2w和6wO+D组大鼠海马区出现了广泛的星形胶质细胞活化。与C组静息态星形胶质细胞细长的突起相比,两组O+D活化的星形胶质细胞胞体肥大,突起增粗深染,呈高度分支状;此外,许多6w O+D组GFAP阳性的星形胶质细胞出现了胞体类似崩解的退行性改变。(6)电镜结果显示6w O+D组大鼠海马内星形胶质细胞出现了糖原颗粒和胶质纤维丝的聚集或缺失、线粒体的肿胀或分布异常为特征的退行性改变。尤其在海马突触密集的区域,水样变性的星形胶质细胞突起高度肿胀,包绕着变性的突触结构。此外,在许多2w和6w O+D组大鼠海马脑毛细血管周围包绕着许多肿胀的星形胶质细胞终足。尤其在6w O+D组大鼠毛细血管内皮细胞出现扭曲变形和空泡化。上述病理改变并没有在C组出现。(7)6w O+D组大鼠的海马及大脑皮质的一些区域出现了血管周围区域HRP的泄漏。而在C组HRP反应产物则分布在血管内,没有明显的外泄。
结论:1.雌激素剥夺和氧化应激在AD发生发展中的协同作用。2.OVX结合注射D-gal可以作为一个较好模拟AD病症的动物模型。3.星形胶质细胞在此模型病变的发生发展中起到了重要作用。
Objective:1.To develop a new multiplicity AD model by long-term intraperitoneal administration of D-gal in OVX rats to further address the synergistic effects of estrogen deprivation and oxidative stress on the development and progression of AD.2.To investigate whether astrocytes are involved in the pathogenesis of this AD model.
Methods:Three-month-old female Sprague-Dawley rats were randomly and equally divided into five groups:the intact control group(C),the OVX and D-gal injected group(O+D),the OVX-only group(O),the sham operated and D-gal injected group(D)and the OVX,D-gal and 17-βestradiol injected group(O+D+E).After six weeks,several behavioral tests as well as ChAT immunohistochemistry of cholinergic neuron in basal forebrain and Aβimmunohistochemistry in hippocampus, observation of electron microscope,ultrastructural analysis of lipofuscin deposition and the density of synapses have been performed to evaluate the success of this AD model.To investigate the involvement of astrocytes in the pathogenesis of this AD model,We detected the expression of GFAP by immunohistochemistry and western-blotting, levels of GSH,ultrastructural changes of the astrocytes,with special attention on astrocytes surrounding the axonal terminals and brain microvessels as well as the permeability of blood-brain barrier by intravascular injection of HRP in the hippocampus in ovariectomized rats injected with D-gal for 2 and 6 weeks respectively.
Results:1.Compared with C groups,behavior and pathology of the rats was prominently impaired in the D,O,O+D and O+D+E groups, especially the O+D groups,versus with which the learning impairment was attenuated significantly in the O+D+E animals.The more serious damages of O+D groups as follows:(1)The mean number of square entries was increased in the open field testing;The training frequency required to attain the learning criterion was markedly increased in the Y-maze;The number of errors was highest and the step-down latency decreased dramatically in step-down type passive avoidance testing.(2) The decreased number of cholinergic neuron suffered atrophy,indicated by the small soma and deficiency of the processes.(3)Many Aβimmunoreactive neurons which absent in the other four groups,were easily detected in the hippocampus mainly located at the pyramidal layer of CA1,subiculum and granular cell layer of the dentate gyrus.(4) Ultrastructural changes:Nuclear degeneration with condensed chromatin aggregated in the rim of the nucleus with a disrupted and incomplete nuclear membrane.Lipofuscin accumulated in the cytoplasm some of which contained granulovacuolar bodies.NFT appeared in the cytoplasm or dendrites of neurons.Some mitochondria showed disrupted cristae and a swollen,twisted or vacuolar appearance.Synapse degeneration was frequently observed in the CA1 region of the hippocampus,the obvious increased lipofuscin and decreased synapses.
2.(1)The 6w O+D rats required longer times to reach the platform than control and 2w experimental rats.The control and 2w O+D rats spent the majority of their time swimming in the quadrant where the platform was located,while the 6w O+D animals tended to spend their time in all quadrants.No statistical differences were observed between the control and 2w O+D groups.(2)6w O+D rats showed a prominent loss of cholinergic terminals and AChE activity in the hippocampus,compared to the control and 2w O+D groups.No significant differences were found between the control and 2w O+D groups.(3)2w and 6w O+D groups showed significant increase in the protein levels of GFAP,compared to the control.No statistical significances were observed between the two O+D groups.(4)The 6w O+D group exhibited significant decrease of GSH levels,compared to the control and 2w groups.A slight increase in GSH levels was observed in the 2w O+D group,but the difference was not significant,relative to the control.(5)Activated astrocytes were widespread in the all regions of the hippocampus in 2w and 6w O+D rats, relative to the controls.These activated glial cells exhibited hypertrophy, with very thick,highly ramified and intensely immunostained branches, compared to resting form with long,slender processes in the controls. Furthermore,many GFAP-positive astrocytes in the 6w O+D rats underwent degeneration,characterized by apparent breakdown of cell bodies.(6)Eelectron microscopy showed that some astrocytes were degeneration in the hippocampus of 6w O+D rats,identified by reduction or devoid of glycogen granules and glial intermediate fibers,and swollen or aberrant appearance of mitochondria.Especially,in the aggregated area of synapse,extremely swollen astrocytic process with watery appearance often engulfed the degenerated synaptic structures.Swollen perivascluar astrocytic endfeet surrounding the brain capillary were frequently observed in both 2w and 6w O+D rats.Especially,in the 6w O+D rats,irregular-shaped microvessels were lined by distorted or vacuolized endothelium.The above pathological changes were not evident in the controls.(7)Perivascular areas of HRP leakages were observed in some regions in the hippocampus or the cerebral cortex of O+D rats,the marker showed an intravascular localization in the controls.
Conclusions:1.These results strongly suggest that estrogen deprivation and oxidative stress behave synergistically to enhance the development and progression of AD.2.OVX combined with D-gal injection may serve as an ideal AD rodent model capable of mimicking pathological,neurochemical and behavioral alterations in AD.3. Biochemical and pathological alterations of astrocytes may partially contribute to exacerbating neuronal deficits in course of this AD model.
方法:1.3月龄雌性SD大鼠,随机分为对照组(C)、OVX结合注射D-gal模型组(O+D)、单纯OVX组(O)、单纯注射D-gal组(D)和17-β雌二醇替代治疗组(O+D+E),6周后进行行为学测定、基底前脑胆碱能神经元ChAT免疫组化染色、海马区Aβ免疫组化染色、海马及皮质电镜超微结构观察和脂褐素与突触的定量分析来验证此模型。2.应用此模型(O+D),以2周和6周为观察时间点,通过海马区GFAP的免疫组化染色和western-blotting检测、GSH的生化检测、AChE组织化学染色与光密度分析及AChE活性测定、突触和血-脑屏障周围超微结构观察以及HRP通透性实验来研究星形胶质细胞在此模型中的病理改变与功能障碍。
结果:1.与C组相比,O+D组、O+D+E组、D组、O组均出现不同程度的行为学和病理学损害,以O+D组损害最为明显,具体表现为:(1)开场实验中,穿越格数明显减少;Y型迷宫达到学会标准的测试次数增多;跳台实验中,错误次数增加、潜伏期缩短。(2)在MS、NDB区域的ChAT免疫阳性胆碱能神经元明显减少,染色变浅,突起变短。(3)在海马的齿状回、CA1和下托观察到了其他组没有出现的细胞内Aβ沉积。(4)超微结构损害:细胞核变形扭曲;核内染色质聚集成不规则的高电子密度的块状;核膜破裂、不完整;胞浆内含有大量脂褐素、次级溶酶体;线粒体出现肿胀扭曲、变形,嵴断裂、空泡样变;细胞质内出现类似NFT改变;大量变性的突触结构。脂褐素数量明显增加,突触数量明显减少。2.(1)与C组和2w O+D组相比,6w O+D组大鼠在水迷宫行为学实验中,到达平台的潜伏期明显延长;穿越平台次数和在目标象限时间明显减少,而C组与2wO+D组大鼠之间没有统计学差异。(2)与C组和2w O+D组大鼠相比,6w O+D组大鼠在海马区出现了明显的胆碱能纤维终末的密度下降与AChE活性降低,而C组与2w O+D组大鼠之间没有统计学差异。(3)与C组相比,2w与6w O+D组大鼠海马区GFAP水平明显增加,但两组间没有统计学差异。(4)与C组和2w O+D组相比,6w O+D组出现了明显的GSH水平的降低。而2w O+D组则观察到了GSH水平的轻度升高,但与C组相比并没有明显的差异。(5)在2w和6wO+D组大鼠海马区出现了广泛的星形胶质细胞活化。与C组静息态星形胶质细胞细长的突起相比,两组O+D活化的星形胶质细胞胞体肥大,突起增粗深染,呈高度分支状;此外,许多6w O+D组GFAP阳性的星形胶质细胞出现了胞体类似崩解的退行性改变。(6)电镜结果显示6w O+D组大鼠海马内星形胶质细胞出现了糖原颗粒和胶质纤维丝的聚集或缺失、线粒体的肿胀或分布异常为特征的退行性改变。尤其在海马突触密集的区域,水样变性的星形胶质细胞突起高度肿胀,包绕着变性的突触结构。此外,在许多2w和6w O+D组大鼠海马脑毛细血管周围包绕着许多肿胀的星形胶质细胞终足。尤其在6w O+D组大鼠毛细血管内皮细胞出现扭曲变形和空泡化。上述病理改变并没有在C组出现。(7)6w O+D组大鼠的海马及大脑皮质的一些区域出现了血管周围区域HRP的泄漏。而在C组HRP反应产物则分布在血管内,没有明显的外泄。
结论:1.雌激素剥夺和氧化应激在AD发生发展中的协同作用。2.OVX结合注射D-gal可以作为一个较好模拟AD病症的动物模型。3.星形胶质细胞在此模型病变的发生发展中起到了重要作用。
Objective:1.To develop a new multiplicity AD model by long-term intraperitoneal administration of D-gal in OVX rats to further address the synergistic effects of estrogen deprivation and oxidative stress on the development and progression of AD.2.To investigate whether astrocytes are involved in the pathogenesis of this AD model.
Methods:Three-month-old female Sprague-Dawley rats were randomly and equally divided into five groups:the intact control group(C),the OVX and D-gal injected group(O+D),the OVX-only group(O),the sham operated and D-gal injected group(D)and the OVX,D-gal and 17-βestradiol injected group(O+D+E).After six weeks,several behavioral tests as well as ChAT immunohistochemistry of cholinergic neuron in basal forebrain and Aβimmunohistochemistry in hippocampus, observation of electron microscope,ultrastructural analysis of lipofuscin deposition and the density of synapses have been performed to evaluate the success of this AD model.To investigate the involvement of astrocytes in the pathogenesis of this AD model,We detected the expression of GFAP by immunohistochemistry and western-blotting, levels of GSH,ultrastructural changes of the astrocytes,with special attention on astrocytes surrounding the axonal terminals and brain microvessels as well as the permeability of blood-brain barrier by intravascular injection of HRP in the hippocampus in ovariectomized rats injected with D-gal for 2 and 6 weeks respectively.
Results:1.Compared with C groups,behavior and pathology of the rats was prominently impaired in the D,O,O+D and O+D+E groups, especially the O+D groups,versus with which the learning impairment was attenuated significantly in the O+D+E animals.The more serious damages of O+D groups as follows:(1)The mean number of square entries was increased in the open field testing;The training frequency required to attain the learning criterion was markedly increased in the Y-maze;The number of errors was highest and the step-down latency decreased dramatically in step-down type passive avoidance testing.(2) The decreased number of cholinergic neuron suffered atrophy,indicated by the small soma and deficiency of the processes.(3)Many Aβimmunoreactive neurons which absent in the other four groups,were easily detected in the hippocampus mainly located at the pyramidal layer of CA1,subiculum and granular cell layer of the dentate gyrus.(4) Ultrastructural changes:Nuclear degeneration with condensed chromatin aggregated in the rim of the nucleus with a disrupted and incomplete nuclear membrane.Lipofuscin accumulated in the cytoplasm some of which contained granulovacuolar bodies.NFT appeared in the cytoplasm or dendrites of neurons.Some mitochondria showed disrupted cristae and a swollen,twisted or vacuolar appearance.Synapse degeneration was frequently observed in the CA1 region of the hippocampus,the obvious increased lipofuscin and decreased synapses.
2.(1)The 6w O+D rats required longer times to reach the platform than control and 2w experimental rats.The control and 2w O+D rats spent the majority of their time swimming in the quadrant where the platform was located,while the 6w O+D animals tended to spend their time in all quadrants.No statistical differences were observed between the control and 2w O+D groups.(2)6w O+D rats showed a prominent loss of cholinergic terminals and AChE activity in the hippocampus,compared to the control and 2w O+D groups.No significant differences were found between the control and 2w O+D groups.(3)2w and 6w O+D groups showed significant increase in the protein levels of GFAP,compared to the control.No statistical significances were observed between the two O+D groups.(4)The 6w O+D group exhibited significant decrease of GSH levels,compared to the control and 2w groups.A slight increase in GSH levels was observed in the 2w O+D group,but the difference was not significant,relative to the control.(5)Activated astrocytes were widespread in the all regions of the hippocampus in 2w and 6w O+D rats, relative to the controls.These activated glial cells exhibited hypertrophy, with very thick,highly ramified and intensely immunostained branches, compared to resting form with long,slender processes in the controls. Furthermore,many GFAP-positive astrocytes in the 6w O+D rats underwent degeneration,characterized by apparent breakdown of cell bodies.(6)Eelectron microscopy showed that some astrocytes were degeneration in the hippocampus of 6w O+D rats,identified by reduction or devoid of glycogen granules and glial intermediate fibers,and swollen or aberrant appearance of mitochondria.Especially,in the aggregated area of synapse,extremely swollen astrocytic process with watery appearance often engulfed the degenerated synaptic structures.Swollen perivascluar astrocytic endfeet surrounding the brain capillary were frequently observed in both 2w and 6w O+D rats.Especially,in the 6w O+D rats,irregular-shaped microvessels were lined by distorted or vacuolized endothelium.The above pathological changes were not evident in the controls.(7)Perivascular areas of HRP leakages were observed in some regions in the hippocampus or the cerebral cortex of O+D rats,the marker showed an intravascular localization in the controls.
Conclusions:1.These results strongly suggest that estrogen deprivation and oxidative stress behave synergistically to enhance the development and progression of AD.2.OVX combined with D-gal injection may serve as an ideal AD rodent model capable of mimicking pathological,neurochemical and behavioral alterations in AD.3. Biochemical and pathological alterations of astrocytes may partially contribute to exacerbating neuronal deficits in course of this AD model.
引文
[1]程琦,程晓娟,姜国鑫.我国阿尔茨海默病流行病学研究[J].Intern Med Concepts Pract,2007,2:70-74.
[2]Blennow K,de Leon MJ,Zetterberg H.Alzheimer's disease.[J].Lancet,2006,368:387-403.
[3]Parihar MS,Hemnani T.Alzheimer's disease pathogenesis and therapeutic interventions[J].J Clin Neurosci,2004,11:456-467.
[4]Selkoe DJ.Alzheimer's disease:genotypes,phenotypes,and treatments[J].Science,1997,275:630-631.
[5]Trojanowski JQ,Schmidt ML,Shin RW,Bramblett GT,Rao D,Lee VM.Altered tau and neurofilament proteins in neuro-degenerative diseases:diagnostic implications for Alzheimer's disease and Lewy body dementias[J].Brain Pathol,1993,3:45-54.
[6]Roses AD.On the metabolism of apolipoprotein E and the Alzheimer Diseases[J].Exp Neurol,1995,132:149-156.
[7]Mattson MP.Pathways towards and away from Alzheimer's disease [J].Nature,2004,430:631-639.
[8]杨建华.阿尔茨海默病病因及发病机制研究进展[J].实用医技杂志,2006,13:3304-3305.
[9]丁正明,宫斌,莫启忠.老年痴呆动物模型研究进展[J].浙江中西医结合杂志,2000,10:638-641.
[10]曾昭毅,杨雨,苗婷,潘娅,王旭东,蒋乃昌.冈田酸对拟AD模 型大鼠海马CA1区Aβ40和nNOS表达的影响[J].中风与神经疾病杂志,2006,6:708-710.
[11]Exley C.A molecular mechanism of aluminium-induced Alzheimer's disease[J].J Inorg Biochem,1999,76:133-140.
[12]Zhu XW,Raina AK,Perry G,Smith MA.Alzheimer disease:the two-hit hypothesis[J].Lancet Neurol,2004,3:219-226.
[13]Honjo H,Kikuchi N,Hosoda T,Kariya K,Kinoshita Y,Iwasa K,Ohkubo T,Tanaka K,Tamura T,Urabe M,Kawata M.Alzheimer's disease and estrogen[J].J Steroid Biochem Mol Biol,2001,76:227-230.
[14]Panidis DK,Matalliotakis IM,Rousso DH,Kourtis AI,Koumantakis EE.The role of estrogen replacement therapy in Alzheimer's disease[J].Eur J Obstet Gynecol Reprod Biol,2001,95:86-91.
[15]Simpkins JW,Green PS,Gridley KE,Singh M,de Fiebre NC,Rajakumar G.Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease[J].Am J Med,1997,103:19S-25S.
[16]Launer L J,Andersen K,Dewey ME,Letermeur L,Ott A,Amaducci LA,Brayne C,Copeland JR,Dartigues JF,Kragh-Sorensen P,Lobo A,Martinez-Lage JM,Stijnen T,Hofman A.Rates and risk factors for dementia and Alzheimer's disease:results from EURODEM pooled analyses[J].EURODEM Incidence Research Group and Work Groups.European Studies of Dementia.Neurology,1999,52:78-84.
[17] Espeland MA, Rapp SR, Shumaker SA. Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study [J]. J Am Med Assoc, 2004, 291: 2959-2968.
[18] Shumaker SA, Legault C, Kuller L, Rapp SR, Thai L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study [J]. J Am Med Assoc, 2004, 291: 2947-2958.
[19] Dykens JA, Moos WH, Howell N. Development of 17 alpha-estradiol as a neuroprotective therapeutic agent: rationale and results from a phase I clinical study [J]. Ann N Y Acad Sci, 2005, 1052: 116-135.
[20] Feng Z, Cheng Y, Zhang JT. Long-term effects of melatonin or 17 beta-estradiol on improving spatial memory performance in cognitively impaired, ovariectomized adult rats [J]. J Pineal Res, 2004, 37: 198-206.
[21] Ohkura T, Isse K, Akazawa K, Hamamoto M, Yaoi Y, Hagino N. Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer type: 7 case reports [J]. Dementia, 1995, 6: 99-107.
[22] Norbury R, Cutter WJ, Compton J, Robertson DM, Craig M, Whitehead M, Murphy DG. The neuroprotective effects of estrogen on the aging brain[J].Exp Gerontol,2003,38:109-117.
[23]吴乐,陈文军.雌激素的神经保护作用及其机理[J].神经解剖学杂志,2005,21:95-97.
[24]Gibbs RB.Impairment of basal forebrain cholinergic neurons associated with aging and long-term loss of ovarian function[J].Exp Neurol,1998,151:289-302.
[25]Murphy DD,Cole NB,Greenberger V,Segal M.Estradiol increases dendritic spine density by reducing GABA neurotransmission in hippocampal neurons[J].J Neurosci,1998,18:2550-2559.
[26]聂伟,张永祥,周金黄.雌激素对卵巢切除大鼠海马长时程增强的影响[J].中国神经科学杂志,2001,17:335-337.
[27]Behl C.Alzheimer's disease and oxidative stress:implications for novel therapeutic approaches[J].Prog Neurobiol,1999,57:301-323.
[28]Casetta I,Govoni V,Granieri E.Oxidative stress,antioxidants and neurodegenerative diseases[J].Curr Pharm Des,2005,11:2033-2052.
[29]Good PF,Werner P,Hsu A,Olanow CW,Perl DP.Evidence for neuronal oxidative damage in Alzheimer's disease[J].Am J Pathol,1996,149:21-28.
[30]Reiter RJ.Oxidative processes and antioxidative defense mechanisms in the aging brain[J].FASEB J,1995,9:526-533.
[31]Schippling S,Kontush A,Arlt S,Buhmann C,Sturenburg HJ,Mann U,Thomsen TM,Beisiegel U.Increased lipoprotein oxidation in Alzheimer's disease [J]. Free Radic Biol Med, 2000, 28: 351-360.
[32] Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF, Kowall N. Oxidative damage in Alzheimer's [J]. Nature, 1996, 382: 120-121.
[33] Lovell MA, Ehmann WD, Butler SM, Markesbery WR. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer's disease [J]. Neurology, 1995, 45: 1594-1601.
[34] Lyras L, Cairns NJ, Jenner P, Halliwell B. An assessment of oxidative damage to proteins, lipids and DNA in brain from patients with Alzheimer's disease [J]. J Neurochem, 1997, 68: 2061-2069.
[35] Mark RJ, Fuson KS, May PC. Characterization of 8-epiprostaglandin F2alpha as a marker of amyloid beta-peptide induced oxidative damage [J]. JNeurochem, 1999, 72: 1146-1153.
[36] Montine KS, Olson SJ, Amarnath V, Whetsell Jr WO, Graham DG, Montine TJ. Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer's disease is associated with inheritance of ApoE4 [J]. Am J Pathol, 1997, 150: 437-443.
[37] Smith CD, Carney JM, Starke Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease [J]. Proc Natl Acad Sci U S A, 1991, 88: 10540-10543.
[38] Holden HM, Rayment I, Thoden JB. Structure and function of enzymes of the Leloir pathway for galactose metabolism [J]. J Biol Chem, 2003,278:43885-43888.
[39] 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]. J Neurosci Res, 2006, 83: 1584-1590.
[40] Chen CF, Lang SY, Zuo PP, Yang N, Wang XQ, Xia C. Effects of D-galactose on the expression of hippocampal peripheral-type benzodiazepine receptor and spatial memory performances in rats [J]. Psychoneuroendocrinology, 2006, 31: 805-811.
[41] Wei HF, Li L, Song QJ, Ai HX, Chu J, Li W. Behavioural study of the D-galactose induced aging model in C57BL/6J mice [J]. Behav Brain Res, 2005, 157:245-251.
[42] Xu XH, Zhao TQ. Effects of puerarin on D-galactose-induced memory deficits in mice [J]. Acta Pharmacol Sin, 2002, 23: 587-590.
[43] Ho SC, Liu JH, Wu RY. Establishment of the mimetic aging effect in mice caused by D-galactose [J]. Biogerontology, 2003, 4: 15-18.
[44] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families [J]. Science, 1993, 261: 921-923.
[45] Drouet B, Pincon-Raymond M, Chambaz J, Pillot T. Molecular basis of Alzheimer's disease [J]. Cell Mol Life Sci, 2000; 57: 705-715.
[46] Behl C, Moosmann B. Oxidative nerve cell death in Alzheimer's disease and stroke: antioxidants as neuroprotective compounds [J]. Biol Chem, 2002, 383:521-536.
[47] Pratico D, Delanty N. Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease [J]. Am J Med, 2000, 109: 577-585.
[48] Zhang C, Wang SZ, Zuo PP, Cui X, Cai J. Protective effect of tetramethylpyrazine on learning and memory function in D-galactose lesioned mice [J]. Chin Med Sci J, 2004, 19: 180-184.
[49] Moosmann B, Behl C. Antioxidants as treatment for neurodegenerative disorders [J]. Expert Opin Investig Drugs, 2002, 11: 1407-1435.
[50] Amantea D, Russo R, Bagetta G, Corasaniti MT. From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens [J]. Pharmacol Res, 2005, 52: 119-132.
[51] Bhavnani BR. Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's [J]. J Steroid Biochem Mol Biol, 2003, 85:473-482.
[52] Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature [J]. Acta Psychiatr Scand, 1987, 76: 465-479.
[53] Gao S, Hendrie HC, Hall KS, Hui S. The relationships between age, sex, and incidence of dementia and Alzheimer disease: a meta-analysis [J]. Arch Gen Psychiatry, 1998, 55: 809-815.
[54] Markham JA, Pych JC, Juraska JM. Ovarian hormone replacement to aged ovariectomized female rats benefits acquisition of the Morris water maze [J]. Horm Behav, 2002, 42: 284-293.
[55] Ransom B, Behar T, Nedergaard M. New roles for astrocytes (stars at last) [J]. Trends Neurosci, 2003, 26: 520-522.
[56] Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier [J]. Nat Rev Neurosci, 2006, 7: 41-53.
[57] Takuma K, Baba A, Matsuda T. Astrocyte apoptosis: implications for neuroprotection [J]. Prog Neurobiol, 2004, 72: 111-127.
[58] Seifert G, Schilling K, Steinhauser C. Astrocyte dysfunction in neurological disorders: a molecular perspective [J]. Nat Rev Neurosci, 2006, 7: 194-206.
[59] Oide T, Kinoshita T, Arima K. Regression stage senile plaques in the natural course of Alzheimer's disease [J]. Neuropathol Appl Neurobiol, 2006, 32: 539-556.
[60] Mohri I, Kadoyama K, Kanekiyo T, Sato Y, Kagitani-Shimono K, Saito Y, Suzuki K, Kudo T, Takeda M, Urade Y, Murayama S, Taniike M. Hematopoietic prostaglandin D synthase and DPI receptor are selectively upregulated in microglia and astrocytes within senile plaques from human patients and in a mouse model of Alzheimer disease [J]. J Neuropathol Exp Neurol, 2007, 66: 469-480.
[61] Sheng JG, Mrak RE, Griffin WS. Glial-neuronal interactions in Alzheimer disease: progressive association of IL-lalpha+ microglia and S100beta+ astrocytes with neurofibrillary tangle stages [J]. J Neuropathol Exp Neurol, 1997, 56: 285-290.
[62] Desai BS, Monahan AJ, Carvey PM, Hendey B. Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy [J]. Cell Transplant, 2007, 16: 285-299.
[63] Gandy S. Estrogen and neurodegeneration [J]. Neurochem Res, 2003, 28: 1003-1008.
[64] Hua X, Lei M, Zhang Y, Ding J, Han Q, Hu G, Xiao M. Long-term D-galactose injection combined with ovariectomy serves as a new rodent model for Alzheimer's disease [J]. Life Sci, 2007, 80: 1897-1905.
[65] Lei DL, Long JM, Hengemihle J, O'Neill J, Manaye KF, Ingram DK, Mouton PR. Effects of estrogen and raloxifene on neuroglia number and morphology in the hippocampus of aged female mice [J]. Neuroscience, 2003,121:659-666.
[66] Ke ZJ, Gibson GE. Selective response of various brain cell types during neurodegeneration induced by mild impairment of oxidative metabolism [J]. Neurochem Int, 2004, 45: 361-369.
[67] O'Brien TS, Svendsen CN, Isacson O, Sofroniew MV. Loss of true blue labelling from the medial septum following transection of the fimbria-fornix: evidence for the death of cholinergic and noncholinergic neurons [J]. Brain Res, 1990, 508: 249-256.
[68] Yamada M, Chiba T, Sasabe J, Nawa M, Tajima H, Niikura T, Terashita K, Aiso S, Kita Y, Matsuoka M, Nishimoto I. Implanted cannula-mediated repetitive administration of Abeta 25-35 into the mouse cerebral ventricle effectively impairs spatial working memory [J]. Behav Brain Res, 2005, 164: 139-146.
[69] Rossner S, Perez-Polo JR, Wiley RG, Schliebs R, Bigl V. Differential expression of immediate early genes in distinct layers of rat cerebral cortex after selective immunolesion of the forebrain cholinergic system [J]. J Neurosci Res, 1994, 38: 282-293.
[70] Schroeter ML, Mertsch K, Giese H, Muller S, Sporbert A, Hickel B, Blasig IE. Astrocytes enhance radical defence in capillary endothelial cells constituting the blood-brain barrier [J]. FEBS Lett, 1999, 449: 241-244.
[71] Dringen R, Hirrlinger J. Glutathione pathways in the brain [J]. Biol Chem, 2003, 384: 505-516.
[72] Pertusa M, Garcia-Matas S, Rodriguez-Farre E, Sanfeliu C, Cristofol R. Astrocytes aged in vitro show a decreased neuroprotective capacity [J]. J Neurochem, 2007, 101: 794-805.
[73] Flores C, Salmaso N, Cain S, Rodaros D, Stewart J. Ovariectomy of adult rats leads to increased expression of astrocytic basic fibroblast growth factor in the ventral tegmental area and in dopaminergic projection regions of the entorhinal and prefrontal cortex [J]. J Neurosci, 1999, 19: 8665-8673.
[74] Martinez L, de Lacalle S. Astrocytic reaction to a lesion, under hormonal deprivation [J]. Neurosci Lett, 2007, 415: 190-193.
[75] Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues [J]. Nat Rev Neurosci, 2005, 6: 626-640.
[76] Hertz L, Hansson E, Ronnback L. Signaling and gene expression in the neuron-glia unit during brain function and dysfunction: Holger Hyden in memoriam [J]. Neurochem Int, 2001, 39: 227-252.
[77] Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, Vitek MP, Hovanesian V, Stopa EG. Microvascular injury and blood-brain barrier leakage in Alzheimer's disease [J]. Neurobiol Aging, 2007, 28: 977-986.
[78] Su GC, Arendash GW, Kalaria RN, Bjugstad KB, Mullan M. Intravascular infusions of soluble beta-amyloid compromise the blood-brain barrier, activate CNS glial cells and induce peripheral hemorrhage [J]. Brain Res, 1999, 818: 105-117.
[79] Aliev G, Seyidova D, Lamb BT, Obrenovich ME, Siedlak SL, Vinters HV, Friedland RP, LaManna JC, Smith MA, Perry G. Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice [J]. Neurol Res, 2003, 25: 665-674.
[80] Nico B, Paola Nicchia G, Frigeri A, Corsi P, Mangieri D, Ribatti D, Svelto M, Roncali L. Altered blood-brain barrier development in dystrophic MDX mice [J]. Neuroscience, 2004, 125: 921-935.
[81] Liedtke W, Edelmann W, Bieri PL, Chiu FC, Cowan NJ, Kucherlapati R, Raine CS. GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelinization [J]. Neuron, 1996,17:607-615.
[82] Pekny M, Johannson CB, Eliasson C, Stakeberg J, Wallen A, Perimann T, Lendah L, Betsholtz C, Berthold CH, Frisen J. Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin [J]. J Cell Biol, 1999, 145: 503-514.
[83] Everitt BJ, Robbins TW. Central cholinergic systems and cognition [J]. Annu Rev Psychol, 1997, 48: 649-684.
[1]Ferri CP,Prince M,Brayne C,et al.Global prevalence of dementia:a Delphi consensus study[J].Lancet,2005,366:2112-2117.
[2]程琦,程晓娟,姜国鑫.我国阿尔茨海默病流行病学研究[J].J Intern Med Concepts Pract,2007,2:70-74.
[3]Torreilles F,Touchan J.Pathogenic theories and intrathecal analysis of the sporadic form of Alzheimer's disease[J].Prog Neurobiol,2002,66:191-203.
[4]Blennow K,Leon MJ,Zetterberg H.Alzheimer's disease[J].Lancet,2006,368:387-403.
[5]Morgan C,Colombres M,Nunez MT,et al.Structure and function of amyloid in Alzheimer's disease[J].Prog Neurobiol,2004,74:323-349.
[6]McKinney M,Jacksonville MC.Brain cholinergic vulnerability:relevance to behavior and disease[J].Biochem Pharmacol,2005,70:1115-1124.
[7]He YS,Yao ZB,Gu YM,et al.NGF promotes collateral sprouting of cholinergic fibers in the septohippocampal cholinergic system of aged rats with fimbria transection[J].Brain Res,1992,586:27-35.
[8]Ben Ari Y,Trembley E,Ollergen OP.The role of epileptic activity in hippocampal and remove cerebral lesions induced by bainic acid[J].Brain Res,1980,9:79-83.
[9]Solroniew MV,Pearson RCA.Degene relation of cholinergic neuron in the basal nuclear fallowing bainic or N-melhyl-D-aspirlic acid application to the cerebral cortex in the rat[J].Protein Res,1985,339:186-189.
[10]Potter PE,Gaughan C,Assouline Y,et al.Lesion of septal hippocampal neurons with 192 IgG-saporin altersfunction of M1muscarinic receptors[J].Neuropharmacology,1999,38:579-586.
[11]Lucker M,Walker LC,Kuo H.Age-related fibrillard deposits in brains of C57BLP6 mice.A review of localization,straining characteristics,and strain specificity[J].Mol Neurobiol,1994,9:125-133.
[12]Woodruff-Pak DS,Trojanowshi JQ.The old rabbit as an animal model:Implications for Alzheimer's disease[J].Neurobiol Aging,1996,17:283-290.
[13]Kuo H,Ingram DK,Walker LC,et al.Similarities in the age-related hippocampal deposition of periodic acid-schiff-positive granules in the senescence accelerated mouse P8 and C57BL/6 mouse strains[J].Neuroscience,1996,74:733-740.
[14]#12
[15]Kohler C,Ebert U,Baumann K,et al.Alzheimer's disease-like neuropathology of gene-targeted APP-SLxPS1 mut mice expressing the amyloid precursor protein at endogenous levels[J].Neurobiol Dis,2005, 20: 528-540.
[16] Callahan MJ, Lipinshi W, Bian F, et al. Augmented senile plaque load in aged female beta-amyloid precursor protein transgenic mice [J]. Am J Pathol, 2001, 158: 797-801.
[17] Games D, Adams D, Alessandrini R, et al. Alzheimer type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein [J]. Nature, 1995, 373: 523-527.
[18] Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Aβ elevation and amyloid plaques in transgenic mice [J]. Science, 1996, 274: 99-102.
[19] Ilvis RS, Strandberg TE, Java K. Apolipoprotem E phenotypes, dementia and mortality in a prospective population sample [J]. J Am Geriatr Soc, 1998, 46: 712-715.
[20] Li T. Recent progress in Alzheimer's disease: animal models lead the way [J]. Drug Discov Today Dis Models, 2004, 1: 145-149.
[21] Chen Y, Lomnitski L, Michaelson DM, et al. Motor and cognitive deficits in apolipoprotem E deficient mice after closed head injury [J]. Neuroscience, 1997, 80: 1255-1262.
[22] Thinakaran G, So M, Omar RA, et al. Endoproteolysis of presenilin-1 and accumulation of processed derivatives in vivo [J]. Neuron, 1996, 16: 181-190.
[23] Borchelt DR. Metabolism of presenilin 1: influence of presenilin 1 on amyloid precursor protein processing [J]. Neurobiol Aging, 1998, 19: 15-18.
[24] Chui DH, Lim GP, Yang F, et al. Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation [J]. Nat Med, 1999, 5: 560-564.
[25] Ballatore C, Lee VM, Trojanowski JQ. Tau mediated neurodegeneration in Alzheimer's disease and related disorders [J]. Nat Rev Neurosci, 2007, 8: 663-672.
[26] Probst A, Gotz J, Wiederhold KH, et al. Axonopathy and amyotrophy in mice transgenic for human four repeat tau protein [J]. Acta Neuropathol, 2000, 99: 469-481.
[27] Gotz J, Chen F, Van Dorpe J, et al. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils [J]. Science, 2001,293: 1491-1495.
[28] Arendt T, Holzer M, Fruth R, et al. Paired helical filament-like phosphorylation of Tau, Deposition of β/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1A and 2A [J]. Neuroscience, 1995, 69: 691-698.
[29] Miu AC, Benga O. Aluminum and Alzheimer's disease: a new look. [J]. J Alzheimer's Dis, 2006, 10: 179-201.
[30] Wei HF, Li L, Song QJ, et al. Behavioural study of the D-galactose induced aging model in C57BL/6J mice [J]. Behav Brain Res, 2005, 157: 245-251.
[31]Ho SC,Liu JH,Wu RY.Establishment of the mimetic aging effect in mice caused by D-galactose[J].Biogerontology,2003,4:15-18.
[32]Xu XH,Zhao TQ.Effects of puerarin on D-galactose-induced memory deficits in mice[J].Acta Pharmacol Sin,2002,23:587-590.
[33]Ghiso J,Frangione B.Amyloidosis and Alzheimer's disease[J].Adv Drug Deliv Rev,2002,54:1539-1551.
[34]LaFerla FM,Oddo S.Alzheimer's disease:Abeta,tau and synaptic dysfunction[J].Trends Mol Med,2005,11:170-176.
[35]沈玉先,杨军,魏伟等.β淀粉样多肽25-35片段诱导的大鼠学习记忆功能障碍[J].中国药理学通报,2001,17:26-29.
[36]Nakagawa Y,Nakamura R,Kase K,et al.Colchicine lesions in the rat hippocampus mimic the alterations of several markers in Alzheimer's disease[J].Brain Res,1987,408:57-64.
[37]De La Torry JC.Critically attained threshold of cerebral hypoperfusion:Can it cause Alzheimer's disease[J].Neurobiol Aging,2000,21:321-342.
[38]曾芳,余曙光,唐勇等.老年性痴呆复合动物模型研究概况(综述)[J].中国神经免疫学和神经病学杂志,2007,14:197-200.
[2]Blennow K,de Leon MJ,Zetterberg H.Alzheimer's disease.[J].Lancet,2006,368:387-403.
[3]Parihar MS,Hemnani T.Alzheimer's disease pathogenesis and therapeutic interventions[J].J Clin Neurosci,2004,11:456-467.
[4]Selkoe DJ.Alzheimer's disease:genotypes,phenotypes,and treatments[J].Science,1997,275:630-631.
[5]Trojanowski JQ,Schmidt ML,Shin RW,Bramblett GT,Rao D,Lee VM.Altered tau and neurofilament proteins in neuro-degenerative diseases:diagnostic implications for Alzheimer's disease and Lewy body dementias[J].Brain Pathol,1993,3:45-54.
[6]Roses AD.On the metabolism of apolipoprotein E and the Alzheimer Diseases[J].Exp Neurol,1995,132:149-156.
[7]Mattson MP.Pathways towards and away from Alzheimer's disease [J].Nature,2004,430:631-639.
[8]杨建华.阿尔茨海默病病因及发病机制研究进展[J].实用医技杂志,2006,13:3304-3305.
[9]丁正明,宫斌,莫启忠.老年痴呆动物模型研究进展[J].浙江中西医结合杂志,2000,10:638-641.
[10]曾昭毅,杨雨,苗婷,潘娅,王旭东,蒋乃昌.冈田酸对拟AD模 型大鼠海马CA1区Aβ40和nNOS表达的影响[J].中风与神经疾病杂志,2006,6:708-710.
[11]Exley C.A molecular mechanism of aluminium-induced Alzheimer's disease[J].J Inorg Biochem,1999,76:133-140.
[12]Zhu XW,Raina AK,Perry G,Smith MA.Alzheimer disease:the two-hit hypothesis[J].Lancet Neurol,2004,3:219-226.
[13]Honjo H,Kikuchi N,Hosoda T,Kariya K,Kinoshita Y,Iwasa K,Ohkubo T,Tanaka K,Tamura T,Urabe M,Kawata M.Alzheimer's disease and estrogen[J].J Steroid Biochem Mol Biol,2001,76:227-230.
[14]Panidis DK,Matalliotakis IM,Rousso DH,Kourtis AI,Koumantakis EE.The role of estrogen replacement therapy in Alzheimer's disease[J].Eur J Obstet Gynecol Reprod Biol,2001,95:86-91.
[15]Simpkins JW,Green PS,Gridley KE,Singh M,de Fiebre NC,Rajakumar G.Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease[J].Am J Med,1997,103:19S-25S.
[16]Launer L J,Andersen K,Dewey ME,Letermeur L,Ott A,Amaducci LA,Brayne C,Copeland JR,Dartigues JF,Kragh-Sorensen P,Lobo A,Martinez-Lage JM,Stijnen T,Hofman A.Rates and risk factors for dementia and Alzheimer's disease:results from EURODEM pooled analyses[J].EURODEM Incidence Research Group and Work Groups.European Studies of Dementia.Neurology,1999,52:78-84.
[17] Espeland MA, Rapp SR, Shumaker SA. Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study [J]. J Am Med Assoc, 2004, 291: 2959-2968.
[18] Shumaker SA, Legault C, Kuller L, Rapp SR, Thai L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study [J]. J Am Med Assoc, 2004, 291: 2947-2958.
[19] Dykens JA, Moos WH, Howell N. Development of 17 alpha-estradiol as a neuroprotective therapeutic agent: rationale and results from a phase I clinical study [J]. Ann N Y Acad Sci, 2005, 1052: 116-135.
[20] Feng Z, Cheng Y, Zhang JT. Long-term effects of melatonin or 17 beta-estradiol on improving spatial memory performance in cognitively impaired, ovariectomized adult rats [J]. J Pineal Res, 2004, 37: 198-206.
[21] Ohkura T, Isse K, Akazawa K, Hamamoto M, Yaoi Y, Hagino N. Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer type: 7 case reports [J]. Dementia, 1995, 6: 99-107.
[22] Norbury R, Cutter WJ, Compton J, Robertson DM, Craig M, Whitehead M, Murphy DG. The neuroprotective effects of estrogen on the aging brain[J].Exp Gerontol,2003,38:109-117.
[23]吴乐,陈文军.雌激素的神经保护作用及其机理[J].神经解剖学杂志,2005,21:95-97.
[24]Gibbs RB.Impairment of basal forebrain cholinergic neurons associated with aging and long-term loss of ovarian function[J].Exp Neurol,1998,151:289-302.
[25]Murphy DD,Cole NB,Greenberger V,Segal M.Estradiol increases dendritic spine density by reducing GABA neurotransmission in hippocampal neurons[J].J Neurosci,1998,18:2550-2559.
[26]聂伟,张永祥,周金黄.雌激素对卵巢切除大鼠海马长时程增强的影响[J].中国神经科学杂志,2001,17:335-337.
[27]Behl C.Alzheimer's disease and oxidative stress:implications for novel therapeutic approaches[J].Prog Neurobiol,1999,57:301-323.
[28]Casetta I,Govoni V,Granieri E.Oxidative stress,antioxidants and neurodegenerative diseases[J].Curr Pharm Des,2005,11:2033-2052.
[29]Good PF,Werner P,Hsu A,Olanow CW,Perl DP.Evidence for neuronal oxidative damage in Alzheimer's disease[J].Am J Pathol,1996,149:21-28.
[30]Reiter RJ.Oxidative processes and antioxidative defense mechanisms in the aging brain[J].FASEB J,1995,9:526-533.
[31]Schippling S,Kontush A,Arlt S,Buhmann C,Sturenburg HJ,Mann U,Thomsen TM,Beisiegel U.Increased lipoprotein oxidation in Alzheimer's disease [J]. Free Radic Biol Med, 2000, 28: 351-360.
[32] Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF, Kowall N. Oxidative damage in Alzheimer's [J]. Nature, 1996, 382: 120-121.
[33] Lovell MA, Ehmann WD, Butler SM, Markesbery WR. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer's disease [J]. Neurology, 1995, 45: 1594-1601.
[34] Lyras L, Cairns NJ, Jenner P, Halliwell B. An assessment of oxidative damage to proteins, lipids and DNA in brain from patients with Alzheimer's disease [J]. J Neurochem, 1997, 68: 2061-2069.
[35] Mark RJ, Fuson KS, May PC. Characterization of 8-epiprostaglandin F2alpha as a marker of amyloid beta-peptide induced oxidative damage [J]. JNeurochem, 1999, 72: 1146-1153.
[36] Montine KS, Olson SJ, Amarnath V, Whetsell Jr WO, Graham DG, Montine TJ. Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer's disease is associated with inheritance of ApoE4 [J]. Am J Pathol, 1997, 150: 437-443.
[37] Smith CD, Carney JM, Starke Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease [J]. Proc Natl Acad Sci U S A, 1991, 88: 10540-10543.
[38] Holden HM, Rayment I, Thoden JB. Structure and function of enzymes of the Leloir pathway for galactose metabolism [J]. J Biol Chem, 2003,278:43885-43888.
[39] 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]. J Neurosci Res, 2006, 83: 1584-1590.
[40] Chen CF, Lang SY, Zuo PP, Yang N, Wang XQ, Xia C. Effects of D-galactose on the expression of hippocampal peripheral-type benzodiazepine receptor and spatial memory performances in rats [J]. Psychoneuroendocrinology, 2006, 31: 805-811.
[41] Wei HF, Li L, Song QJ, Ai HX, Chu J, Li W. Behavioural study of the D-galactose induced aging model in C57BL/6J mice [J]. Behav Brain Res, 2005, 157:245-251.
[42] Xu XH, Zhao TQ. Effects of puerarin on D-galactose-induced memory deficits in mice [J]. Acta Pharmacol Sin, 2002, 23: 587-590.
[43] Ho SC, Liu JH, Wu RY. Establishment of the mimetic aging effect in mice caused by D-galactose [J]. Biogerontology, 2003, 4: 15-18.
[44] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families [J]. Science, 1993, 261: 921-923.
[45] Drouet B, Pincon-Raymond M, Chambaz J, Pillot T. Molecular basis of Alzheimer's disease [J]. Cell Mol Life Sci, 2000; 57: 705-715.
[46] Behl C, Moosmann B. Oxidative nerve cell death in Alzheimer's disease and stroke: antioxidants as neuroprotective compounds [J]. Biol Chem, 2002, 383:521-536.
[47] Pratico D, Delanty N. Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease [J]. Am J Med, 2000, 109: 577-585.
[48] Zhang C, Wang SZ, Zuo PP, Cui X, Cai J. Protective effect of tetramethylpyrazine on learning and memory function in D-galactose lesioned mice [J]. Chin Med Sci J, 2004, 19: 180-184.
[49] Moosmann B, Behl C. Antioxidants as treatment for neurodegenerative disorders [J]. Expert Opin Investig Drugs, 2002, 11: 1407-1435.
[50] Amantea D, Russo R, Bagetta G, Corasaniti MT. From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens [J]. Pharmacol Res, 2005, 52: 119-132.
[51] Bhavnani BR. Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's [J]. J Steroid Biochem Mol Biol, 2003, 85:473-482.
[52] Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature [J]. Acta Psychiatr Scand, 1987, 76: 465-479.
[53] Gao S, Hendrie HC, Hall KS, Hui S. The relationships between age, sex, and incidence of dementia and Alzheimer disease: a meta-analysis [J]. Arch Gen Psychiatry, 1998, 55: 809-815.
[54] Markham JA, Pych JC, Juraska JM. Ovarian hormone replacement to aged ovariectomized female rats benefits acquisition of the Morris water maze [J]. Horm Behav, 2002, 42: 284-293.
[55] Ransom B, Behar T, Nedergaard M. New roles for astrocytes (stars at last) [J]. Trends Neurosci, 2003, 26: 520-522.
[56] Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier [J]. Nat Rev Neurosci, 2006, 7: 41-53.
[57] Takuma K, Baba A, Matsuda T. Astrocyte apoptosis: implications for neuroprotection [J]. Prog Neurobiol, 2004, 72: 111-127.
[58] Seifert G, Schilling K, Steinhauser C. Astrocyte dysfunction in neurological disorders: a molecular perspective [J]. Nat Rev Neurosci, 2006, 7: 194-206.
[59] Oide T, Kinoshita T, Arima K. Regression stage senile plaques in the natural course of Alzheimer's disease [J]. Neuropathol Appl Neurobiol, 2006, 32: 539-556.
[60] Mohri I, Kadoyama K, Kanekiyo T, Sato Y, Kagitani-Shimono K, Saito Y, Suzuki K, Kudo T, Takeda M, Urade Y, Murayama S, Taniike M. Hematopoietic prostaglandin D synthase and DPI receptor are selectively upregulated in microglia and astrocytes within senile plaques from human patients and in a mouse model of Alzheimer disease [J]. J Neuropathol Exp Neurol, 2007, 66: 469-480.
[61] Sheng JG, Mrak RE, Griffin WS. Glial-neuronal interactions in Alzheimer disease: progressive association of IL-lalpha+ microglia and S100beta+ astrocytes with neurofibrillary tangle stages [J]. J Neuropathol Exp Neurol, 1997, 56: 285-290.
[62] Desai BS, Monahan AJ, Carvey PM, Hendey B. Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy [J]. Cell Transplant, 2007, 16: 285-299.
[63] Gandy S. Estrogen and neurodegeneration [J]. Neurochem Res, 2003, 28: 1003-1008.
[64] Hua X, Lei M, Zhang Y, Ding J, Han Q, Hu G, Xiao M. Long-term D-galactose injection combined with ovariectomy serves as a new rodent model for Alzheimer's disease [J]. Life Sci, 2007, 80: 1897-1905.
[65] Lei DL, Long JM, Hengemihle J, O'Neill J, Manaye KF, Ingram DK, Mouton PR. Effects of estrogen and raloxifene on neuroglia number and morphology in the hippocampus of aged female mice [J]. Neuroscience, 2003,121:659-666.
[66] Ke ZJ, Gibson GE. Selective response of various brain cell types during neurodegeneration induced by mild impairment of oxidative metabolism [J]. Neurochem Int, 2004, 45: 361-369.
[67] O'Brien TS, Svendsen CN, Isacson O, Sofroniew MV. Loss of true blue labelling from the medial septum following transection of the fimbria-fornix: evidence for the death of cholinergic and noncholinergic neurons [J]. Brain Res, 1990, 508: 249-256.
[68] Yamada M, Chiba T, Sasabe J, Nawa M, Tajima H, Niikura T, Terashita K, Aiso S, Kita Y, Matsuoka M, Nishimoto I. Implanted cannula-mediated repetitive administration of Abeta 25-35 into the mouse cerebral ventricle effectively impairs spatial working memory [J]. Behav Brain Res, 2005, 164: 139-146.
[69] Rossner S, Perez-Polo JR, Wiley RG, Schliebs R, Bigl V. Differential expression of immediate early genes in distinct layers of rat cerebral cortex after selective immunolesion of the forebrain cholinergic system [J]. J Neurosci Res, 1994, 38: 282-293.
[70] Schroeter ML, Mertsch K, Giese H, Muller S, Sporbert A, Hickel B, Blasig IE. Astrocytes enhance radical defence in capillary endothelial cells constituting the blood-brain barrier [J]. FEBS Lett, 1999, 449: 241-244.
[71] Dringen R, Hirrlinger J. Glutathione pathways in the brain [J]. Biol Chem, 2003, 384: 505-516.
[72] Pertusa M, Garcia-Matas S, Rodriguez-Farre E, Sanfeliu C, Cristofol R. Astrocytes aged in vitro show a decreased neuroprotective capacity [J]. J Neurochem, 2007, 101: 794-805.
[73] Flores C, Salmaso N, Cain S, Rodaros D, Stewart J. Ovariectomy of adult rats leads to increased expression of astrocytic basic fibroblast growth factor in the ventral tegmental area and in dopaminergic projection regions of the entorhinal and prefrontal cortex [J]. J Neurosci, 1999, 19: 8665-8673.
[74] Martinez L, de Lacalle S. Astrocytic reaction to a lesion, under hormonal deprivation [J]. Neurosci Lett, 2007, 415: 190-193.
[75] Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues [J]. Nat Rev Neurosci, 2005, 6: 626-640.
[76] Hertz L, Hansson E, Ronnback L. Signaling and gene expression in the neuron-glia unit during brain function and dysfunction: Holger Hyden in memoriam [J]. Neurochem Int, 2001, 39: 227-252.
[77] Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, Vitek MP, Hovanesian V, Stopa EG. Microvascular injury and blood-brain barrier leakage in Alzheimer's disease [J]. Neurobiol Aging, 2007, 28: 977-986.
[78] Su GC, Arendash GW, Kalaria RN, Bjugstad KB, Mullan M. Intravascular infusions of soluble beta-amyloid compromise the blood-brain barrier, activate CNS glial cells and induce peripheral hemorrhage [J]. Brain Res, 1999, 818: 105-117.
[79] Aliev G, Seyidova D, Lamb BT, Obrenovich ME, Siedlak SL, Vinters HV, Friedland RP, LaManna JC, Smith MA, Perry G. Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice [J]. Neurol Res, 2003, 25: 665-674.
[80] Nico B, Paola Nicchia G, Frigeri A, Corsi P, Mangieri D, Ribatti D, Svelto M, Roncali L. Altered blood-brain barrier development in dystrophic MDX mice [J]. Neuroscience, 2004, 125: 921-935.
[81] Liedtke W, Edelmann W, Bieri PL, Chiu FC, Cowan NJ, Kucherlapati R, Raine CS. GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelinization [J]. Neuron, 1996,17:607-615.
[82] Pekny M, Johannson CB, Eliasson C, Stakeberg J, Wallen A, Perimann T, Lendah L, Betsholtz C, Berthold CH, Frisen J. Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin [J]. J Cell Biol, 1999, 145: 503-514.
[83] Everitt BJ, Robbins TW. Central cholinergic systems and cognition [J]. Annu Rev Psychol, 1997, 48: 649-684.
[1]Ferri CP,Prince M,Brayne C,et al.Global prevalence of dementia:a Delphi consensus study[J].Lancet,2005,366:2112-2117.
[2]程琦,程晓娟,姜国鑫.我国阿尔茨海默病流行病学研究[J].J Intern Med Concepts Pract,2007,2:70-74.
[3]Torreilles F,Touchan J.Pathogenic theories and intrathecal analysis of the sporadic form of Alzheimer's disease[J].Prog Neurobiol,2002,66:191-203.
[4]Blennow K,Leon MJ,Zetterberg H.Alzheimer's disease[J].Lancet,2006,368:387-403.
[5]Morgan C,Colombres M,Nunez MT,et al.Structure and function of amyloid in Alzheimer's disease[J].Prog Neurobiol,2004,74:323-349.
[6]McKinney M,Jacksonville MC.Brain cholinergic vulnerability:relevance to behavior and disease[J].Biochem Pharmacol,2005,70:1115-1124.
[7]He YS,Yao ZB,Gu YM,et al.NGF promotes collateral sprouting of cholinergic fibers in the septohippocampal cholinergic system of aged rats with fimbria transection[J].Brain Res,1992,586:27-35.
[8]Ben Ari Y,Trembley E,Ollergen OP.The role of epileptic activity in hippocampal and remove cerebral lesions induced by bainic acid[J].Brain Res,1980,9:79-83.
[9]Solroniew MV,Pearson RCA.Degene relation of cholinergic neuron in the basal nuclear fallowing bainic or N-melhyl-D-aspirlic acid application to the cerebral cortex in the rat[J].Protein Res,1985,339:186-189.
[10]Potter PE,Gaughan C,Assouline Y,et al.Lesion of septal hippocampal neurons with 192 IgG-saporin altersfunction of M1muscarinic receptors[J].Neuropharmacology,1999,38:579-586.
[11]Lucker M,Walker LC,Kuo H.Age-related fibrillard deposits in brains of C57BLP6 mice.A review of localization,straining characteristics,and strain specificity[J].Mol Neurobiol,1994,9:125-133.
[12]Woodruff-Pak DS,Trojanowshi JQ.The old rabbit as an animal model:Implications for Alzheimer's disease[J].Neurobiol Aging,1996,17:283-290.
[13]Kuo H,Ingram DK,Walker LC,et al.Similarities in the age-related hippocampal deposition of periodic acid-schiff-positive granules in the senescence accelerated mouse P8 and C57BL/6 mouse strains[J].Neuroscience,1996,74:733-740.
[14]#12
[15]Kohler C,Ebert U,Baumann K,et al.Alzheimer's disease-like neuropathology of gene-targeted APP-SLxPS1 mut mice expressing the amyloid precursor protein at endogenous levels[J].Neurobiol Dis,2005, 20: 528-540.
[16] Callahan MJ, Lipinshi W, Bian F, et al. Augmented senile plaque load in aged female beta-amyloid precursor protein transgenic mice [J]. Am J Pathol, 2001, 158: 797-801.
[17] Games D, Adams D, Alessandrini R, et al. Alzheimer type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein [J]. Nature, 1995, 373: 523-527.
[18] Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Aβ elevation and amyloid plaques in transgenic mice [J]. Science, 1996, 274: 99-102.
[19] Ilvis RS, Strandberg TE, Java K. Apolipoprotem E phenotypes, dementia and mortality in a prospective population sample [J]. J Am Geriatr Soc, 1998, 46: 712-715.
[20] Li T. Recent progress in Alzheimer's disease: animal models lead the way [J]. Drug Discov Today Dis Models, 2004, 1: 145-149.
[21] Chen Y, Lomnitski L, Michaelson DM, et al. Motor and cognitive deficits in apolipoprotem E deficient mice after closed head injury [J]. Neuroscience, 1997, 80: 1255-1262.
[22] Thinakaran G, So M, Omar RA, et al. Endoproteolysis of presenilin-1 and accumulation of processed derivatives in vivo [J]. Neuron, 1996, 16: 181-190.
[23] Borchelt DR. Metabolism of presenilin 1: influence of presenilin 1 on amyloid precursor protein processing [J]. Neurobiol Aging, 1998, 19: 15-18.
[24] Chui DH, Lim GP, Yang F, et al. Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation [J]. Nat Med, 1999, 5: 560-564.
[25] Ballatore C, Lee VM, Trojanowski JQ. Tau mediated neurodegeneration in Alzheimer's disease and related disorders [J]. Nat Rev Neurosci, 2007, 8: 663-672.
[26] Probst A, Gotz J, Wiederhold KH, et al. Axonopathy and amyotrophy in mice transgenic for human four repeat tau protein [J]. Acta Neuropathol, 2000, 99: 469-481.
[27] Gotz J, Chen F, Van Dorpe J, et al. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils [J]. Science, 2001,293: 1491-1495.
[28] Arendt T, Holzer M, Fruth R, et al. Paired helical filament-like phosphorylation of Tau, Deposition of β/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1A and 2A [J]. Neuroscience, 1995, 69: 691-698.
[29] Miu AC, Benga O. Aluminum and Alzheimer's disease: a new look. [J]. J Alzheimer's Dis, 2006, 10: 179-201.
[30] Wei HF, Li L, Song QJ, et al. Behavioural study of the D-galactose induced aging model in C57BL/6J mice [J]. Behav Brain Res, 2005, 157: 245-251.
[31]Ho SC,Liu JH,Wu RY.Establishment of the mimetic aging effect in mice caused by D-galactose[J].Biogerontology,2003,4:15-18.
[32]Xu XH,Zhao TQ.Effects of puerarin on D-galactose-induced memory deficits in mice[J].Acta Pharmacol Sin,2002,23:587-590.
[33]Ghiso J,Frangione B.Amyloidosis and Alzheimer's disease[J].Adv Drug Deliv Rev,2002,54:1539-1551.
[34]LaFerla FM,Oddo S.Alzheimer's disease:Abeta,tau and synaptic dysfunction[J].Trends Mol Med,2005,11:170-176.
[35]沈玉先,杨军,魏伟等.β淀粉样多肽25-35片段诱导的大鼠学习记忆功能障碍[J].中国药理学通报,2001,17:26-29.
[36]Nakagawa Y,Nakamura R,Kase K,et al.Colchicine lesions in the rat hippocampus mimic the alterations of several markers in Alzheimer's disease[J].Brain Res,1987,408:57-64.
[37]De La Torry JC.Critically attained threshold of cerebral hypoperfusion:Can it cause Alzheimer's disease[J].Neurobiol Aging,2000,21:321-342.
[38]曾芳,余曙光,唐勇等.老年性痴呆复合动物模型研究概况(综述)[J].中国神经免疫学和神经病学杂志,2007,14:197-200.