GLP-1对STZ诱导的实验大鼠行为学损伤和τ过磷酸化的保护作用
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摘要
研究背景：一些胰高血糖素样多肽1 (Glucagon-like peptide-1,GLP-1)人工合成类似物可在一定程度上治疗糖尿病。GLP-1受体在脑内有广泛的分布,GLP-1还具有神经保护作用。又由于糖尿病与AD间存在诸多相似之处,所以对GLP-1治疗AD可能性的研究对开发治疗AD新药具有重要意义。
目的：GLP-1对链尿佐菌素(Streptozocin, STZ)所诱导的阿尔茨海默病(Alzheimer Disease, AD)样大鼠实验动物模型在行为学和Tau蛋白病理学的作用。方法：24只雄性Wistar大鼠,体重250g±10g,随机平均分成对照组、STZ组和GLP-1保护组：对照组侧脑室注射10μl的生理盐水；STZ组侧脑室注射10μl用生理盐水溶解的STZ; GLP-1组侧脑室先后分别依次注射生理盐水溶解的10μl的STZ和10μl的GLP-1。2周后,用Morris水迷宫(Morris Water Maze, MWM)检测各组大鼠的学习、记忆情况；3周后,取各组大鼠的海马组织,用蛋白质印迹技术检测大鼠海马组织的磷酸化Tau蛋白与总Tau蛋白的表达情况。
结果：
1.MWM定位航行实验示：在第1、2、4、5天的实验中,STZ组分别与对照组和GLP-1组大鼠相比较,其逃避潜伏期明显较其他两组的长,差异有非常显著意义(p<0.05)；并且在此实验中,对照组与GLP-1组间相比较,它们的逃避潜伏期无统计学差异(除第3天外,p=0.02)。表明STZ组大鼠学习能力的确已下降,而GLP-1组大鼠的学习能力较STZ组有明显改善。从连续5天的实验纵向来看,对照组和GLP-1组的大鼠在第3天后,它们的逃避潜伏期几乎已进饱和期；而STZ组大鼠的逃避潜伏期仍有继续缩短的趋势。
2.MWM空间探索实验示：对照组、GLP-1组与STZ组相比,其在原平台象限的时间比例明显都比STZ组大,差异有统计学意义(p<0.05)；GLP-1组、STZ组与对照组相比,又均比对照组的比例小,差异也有统计学意义(p<0.05)。表明STZ组大鼠记忆能力的确已下降；而GLP-1组大鼠的记忆能力较STZ组有所改善,但未彻底改善。
3.蛋白质印迹结果显示三组大鼠海马神经元的总Tau蛋白的表达水平没有显著差异。而STZ组大鼠海马神经元的磷酸化Tau蛋白的表达量明显增高,相比而言,对照组和GLP-1组的要低些。但是对照组与GLP-1组相比,对照组的表达量还要低,差异均有统计学意义(p<0.05)。而体现三组的差异性,是通过各组的P-Tau与总Tau的灰度值的比值来实现的。
结论：GLP-1能改善STZ诱导的损伤大鼠的学习记忆功能,并能抑制Tau蛋白的过度磷酸化。
Background:Some Glucagon-like peptide-1 (GLP-1) synthetic analogue can give a good treatment on diabetes to some extent. GLP-1 also have the neuroprotective effect and its receptor have an extensively distributation in brain. And Considering some similarities between AD and diabetes, it is important to research the effect of GLP-1 in treating AD.
Objective:To study protective effect of GLP-1 on behavior and Tau phosphoralation in rats treated by streptozocin (STZ).
Methods:Twenty-four Wistar male rats,250g±l0g, were randomly divided into three groups:Control group, STZ group and GLP-1 protecting group. Then began building the AD model. The control rats were intracerebroventricular (i.c.v)-injected with 10 ul saline. The STZ-rats were i.c.v-injected with 10 ul STZ dissolved in saline, and the GLP-1-rats were i.c.v-injected with 10 ul GLP-1 in the rats treated by 10 ul STZ beforehand. GLP-1 and STZ were dissolved in saline. Two weeks later, the ability of learning and memory of each group rats were detected by Morris water maze (MWM). Three weeks later, the expression of phosphorylation Tau (P-Tau) and total Tau in hippocampus tissues were analyzed by Western blot.
Result:
1. The place navigation test of MWM showed:In the first, second, fourth and fifth day's experiments, the escape latencies of STZ group were significantly longer than the other two groups, and there was significant difference (p<0.05). But in the experimentes, the escape latencies between control group and GLP-1 group had no significant difference (except for the third day, p= 0.02). The experiment showed that STZ group's learning ability had indeed declined and GLP-1 group's learning ability had improved significantly compared with STZ group. Observing from the five consecutive days'experiments, control and GLP-1 groups' escape latency were almost into the saturation phase, while STZ rats'escape latency still had the possibility of to shorten.
2. The space exploration test of MWM test showed:control group and GLP-1 group had a larger proportion of time in original platform quadrant as compared with STZ group.The difference had statistically significant (p<0.05). GLP-1 group and STZ group, had a shorter proportion of time in original platform quadrant as compared with control group. The difference also had statistically significant (p<0.05). The experiment showed that STZ group's memory ability had indeed declined and GLP-1 group's memory ability had improved significantly compared with STZ group but not thoroughly.
3. Western blot results showed that there are not significant difference in total Tau protein levels among three groups rats' hippocampal neurons. The expression of phosphorylated Tau protein in STZ group rats hippocampal neurons had a significantly increase compared with control group and GLP-1 group (p< 0.05). The difference of three groups are reflected by the ratio of P-Tau/the total Tau protein gray value.
Conclusion:GLP-1 can enhance the ability of learning and memory of the rats treated by STZ, and can inhibit the hyperphosphorylation of Tau protein induced by STZ.
目的：GLP-1对链尿佐菌素(Streptozocin, STZ)所诱导的阿尔茨海默病(Alzheimer Disease, AD)样大鼠实验动物模型在行为学和Tau蛋白病理学的作用。方法：24只雄性Wistar大鼠,体重250g±10g,随机平均分成对照组、STZ组和GLP-1保护组：对照组侧脑室注射10μl的生理盐水；STZ组侧脑室注射10μl用生理盐水溶解的STZ; GLP-1组侧脑室先后分别依次注射生理盐水溶解的10μl的STZ和10μl的GLP-1。2周后,用Morris水迷宫(Morris Water Maze, MWM)检测各组大鼠的学习、记忆情况；3周后,取各组大鼠的海马组织,用蛋白质印迹技术检测大鼠海马组织的磷酸化Tau蛋白与总Tau蛋白的表达情况。
结果：
1.MWM定位航行实验示：在第1、2、4、5天的实验中,STZ组分别与对照组和GLP-1组大鼠相比较,其逃避潜伏期明显较其他两组的长,差异有非常显著意义(p<0.05)；并且在此实验中,对照组与GLP-1组间相比较,它们的逃避潜伏期无统计学差异(除第3天外,p=0.02)。表明STZ组大鼠学习能力的确已下降,而GLP-1组大鼠的学习能力较STZ组有明显改善。从连续5天的实验纵向来看,对照组和GLP-1组的大鼠在第3天后,它们的逃避潜伏期几乎已进饱和期；而STZ组大鼠的逃避潜伏期仍有继续缩短的趋势。
2.MWM空间探索实验示：对照组、GLP-1组与STZ组相比,其在原平台象限的时间比例明显都比STZ组大,差异有统计学意义(p<0.05)；GLP-1组、STZ组与对照组相比,又均比对照组的比例小,差异也有统计学意义(p<0.05)。表明STZ组大鼠记忆能力的确已下降；而GLP-1组大鼠的记忆能力较STZ组有所改善,但未彻底改善。
3.蛋白质印迹结果显示三组大鼠海马神经元的总Tau蛋白的表达水平没有显著差异。而STZ组大鼠海马神经元的磷酸化Tau蛋白的表达量明显增高,相比而言,对照组和GLP-1组的要低些。但是对照组与GLP-1组相比,对照组的表达量还要低,差异均有统计学意义(p<0.05)。而体现三组的差异性,是通过各组的P-Tau与总Tau的灰度值的比值来实现的。
结论：GLP-1能改善STZ诱导的损伤大鼠的学习记忆功能,并能抑制Tau蛋白的过度磷酸化。
Background:Some Glucagon-like peptide-1 (GLP-1) synthetic analogue can give a good treatment on diabetes to some extent. GLP-1 also have the neuroprotective effect and its receptor have an extensively distributation in brain. And Considering some similarities between AD and diabetes, it is important to research the effect of GLP-1 in treating AD.
Objective:To study protective effect of GLP-1 on behavior and Tau phosphoralation in rats treated by streptozocin (STZ).
Methods:Twenty-four Wistar male rats,250g±l0g, were randomly divided into three groups:Control group, STZ group and GLP-1 protecting group. Then began building the AD model. The control rats were intracerebroventricular (i.c.v)-injected with 10 ul saline. The STZ-rats were i.c.v-injected with 10 ul STZ dissolved in saline, and the GLP-1-rats were i.c.v-injected with 10 ul GLP-1 in the rats treated by 10 ul STZ beforehand. GLP-1 and STZ were dissolved in saline. Two weeks later, the ability of learning and memory of each group rats were detected by Morris water maze (MWM). Three weeks later, the expression of phosphorylation Tau (P-Tau) and total Tau in hippocampus tissues were analyzed by Western blot.
Result:
1. The place navigation test of MWM showed:In the first, second, fourth and fifth day's experiments, the escape latencies of STZ group were significantly longer than the other two groups, and there was significant difference (p<0.05). But in the experimentes, the escape latencies between control group and GLP-1 group had no significant difference (except for the third day, p= 0.02). The experiment showed that STZ group's learning ability had indeed declined and GLP-1 group's learning ability had improved significantly compared with STZ group. Observing from the five consecutive days'experiments, control and GLP-1 groups' escape latency were almost into the saturation phase, while STZ rats'escape latency still had the possibility of to shorten.
2. The space exploration test of MWM test showed:control group and GLP-1 group had a larger proportion of time in original platform quadrant as compared with STZ group.The difference had statistically significant (p<0.05). GLP-1 group and STZ group, had a shorter proportion of time in original platform quadrant as compared with control group. The difference also had statistically significant (p<0.05). The experiment showed that STZ group's memory ability had indeed declined and GLP-1 group's memory ability had improved significantly compared with STZ group but not thoroughly.
3. Western blot results showed that there are not significant difference in total Tau protein levels among three groups rats' hippocampal neurons. The expression of phosphorylated Tau protein in STZ group rats hippocampal neurons had a significantly increase compared with control group and GLP-1 group (p< 0.05). The difference of three groups are reflected by the ratio of P-Tau/the total Tau protein gray value.
Conclusion:GLP-1 can enhance the ability of learning and memory of the rats treated by STZ, and can inhibit the hyperphosphorylation of Tau protein induced by STZ.
引文
[1]Li L, Christian H. Common pathological processes in Alzheimer disease and type 2 diabetes: A review. Brain Research Reviews,2007,56(2):384-402.
[2]Fatma KD, Belgin SD, Melek O. Protective effects of a calcium channel blocker on apoptosis in thymus of neonatal STZ-diabetic rats. Acta histochemica,2005,107(3):207-214.
[3]Rahul A, Ethika T, Rakesh S, etc. A study of brain insulin receptors, AChE activity and oxidative stress in rat model of ICV STZ induced dementia. Neuropharmacology,2009,56(4): 779-787.
[4]D.K. Arulmozhia, B. Portha. GLP-1 based therapy for type 2 diabetes. European Journal Of Pharmaceutical Sciences,2006,28(1-2):96-108.
[5]Subhas CB, Jean B, Lloyd AG. Glucagon-like Peptide-1 (GLP-1) Diminishes Neuronal Degeneration and Death Caused by NGF Deprivation by Suppressing Bim Induction. Neurochem Research,2008,33(9):1845-1851.
[6]Qin ZX, Sun ZW, Huang J. Mutated recombinant human glucagon-like peptide-1 protects SH-SY5Y cells from apoptosis induced by amyloid-β peptide (1-42). Neuroscience Letters, 2008,444(3):217-221.
[7]Victor A.G, Christian H. GLP-1 agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. European Journal of Pharmacology,2008,587 (1-3):112-117.
[8]诸葛启钏.大鼠脑立体定位图谱.(第三版).北京：人民卫生出版社,2005：图10-图36.
[9]Takashi I, Manabu S, Kazuma K, et al. The influences of juvenile diabetes on memory and hippocampal plasticity in rats:Improving effects of glucagon-like peptide-1. Neuroscience Research,2009,64 (1):67-74.
[10]Natalia S, Yan J, Eliezer G,et al. NAP protects memory, increases soluble tau and reduces tau hyperphosphorylation in a tauopathy model. Neurobiology of Disease,2009,34(2):381-388.
[11]Jesus A.Tau phosphorylation and aggregation in Alzheimer's disease pathology. FEBS Letters,2006,580(12):2922-2927.
[12]胡镜清,温泽淮,赖世隆.Morris水迷宫检测的记忆属性与方法学初探.广州中医药大学学报,2000,17(2)：117-119.
[13]朱大年,吴博威,樊小力,等.生理学(第七版).北京：人民卫生出版社,2008,327-329.
[14]Martins IJ, Hone E, Foster JK, et al. Apolipoprotein E, cholesterolmetabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry,2006,11 (8):721-736.
[15]Biessels GJ, Kappelle LJ. Increased risk of Alzheimer's disease in Type II diabetes:insulin resistance of the brain or insulin-induced amyloid pathology. Biochem Soc Trans,2005,33 (5):1041-1044.
[16]Lester-Coll N, Rivera EJ, Soscia SJ, et al. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis,2006,9 (1):13-33.
[17]曾望远,董克礼.AD的病因机制研究概况.湖南中医杂志,2006,22(1)：77-80.
[18]M.A. Orlovsky, F.Spiga, Y.V.Lebed, et al. Early Molecular Events in the Hippocampus of Rats with Streptozotocin-Induced Diabetes. Neurophsiology,2007,39(6):498-502.
[19]Nataniel L, Enrique J.R, Stephanie J.S, et al. Intracerebral streptozotocin model of type 3 diabetes:Relevance to sporadic Alzheimer's disease. Journal of Alzheimer's Disease,2006, 9(1):13-33.
[20]Rudi DH, Peter P.D. Applications of the Morris water maze in the study of learning and memory. Brain Research Reviews,2001,36(1):60-90.
[1]Butterfield DA, Reed T, Newman SF,et al. Roles of amyloid β-pep-tide-associated oxidative stress and brain p rotein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Free Radical Biology&Medicine,2007,43(5):658-677.
[2]侯佳宁,胡雅儿.阿尔茨海默病淀粉样肽级联假说及其相关基因研究进展[J].神经解剖学杂志,2009,25(1)：111-114.
[3]张婧.早发性痴呆相关基因的研究.实用医学杂志,2008,24(21)：3781-3783.
[4]Yu ZF, Cheng GJ, Hu BR. Mechamism of coloicine impairment on learning and memory, and protective effect of CGP36742 in mice. Brain Research,1997,750 (1):53-59.
[5]曾望远,董克礼.AD的病因机制研究概况.湖南中医杂志,2006,22(1)：77-80.
[6]Liu R, Wang JZ. Protein phosphatase-2A in Alzheimer's disease. Pathophysiolog,2009,16 (4):273-277.
[7]Drewes, G., Ebneth, A. and Mandelkow, E.M. MAPs,MARKs and microtubule dynamics.Trends in Biochemical Science,1998,23 (80);307-311.
[8]Liu T, Li Y. Cholesterol in the pathogenesis of Alzheiner's disease. International Journal of Pathology and Clinical Medicine,2008,28(1):81-84.
[9]朱洪山.脂质代谢在阿尔茨海默病发病机制中的研究进展.重庆医学,2009,38(3)：347-350.
[10]Xie CL, Lund EG, Stephen D, et al. Quantitation of two pathyways for cholesterol excretion from the brain normal mice and mice with neurodegeneration. Journal of Lipid Research, 2003,44(9):1780-1789.
[11]Oddo S, Vasilevko V, Caccamo A, et al. Reduction of soluble Aβ and Tau, but not soluble Aβ alone, ameliorates cognitive decline in transgenic mice with p laques and tangles. J Biol Chem,2006,281(51):39413-39423.
[12]Burn M, Duff K. Cholesterol in Alzheimer's disease and tauopathy. Ann NY Acad Sci, 2002,977(6):367-375.
[13]Distl R, Meske V, Ohm TG. Tangle2bearing neurons contain more free cholesterol than adjacent tangle2free neurons. Acta Neuropathol,2001,101(6):547-554.
[14]Antero S, Johanna O, Anu K, et al. Inflammation in Alzheimer's disease: Amyloid-βoligomers trigger innate immunity defence via pattern recognition receptors. Progress in Neurobiology,2009,87(3):181 - 194.
[15]Angela R.K, Ronald G.C, Ananda P.D, et al. Inflammation and Alzheimer's disease: Possible role of periodontal diseases. Alzheimer's and Dementia,2008,4(4)242-250.
[16]Sobotka T.J, Whittaker P, Sobotka J.M, et al. Neurobehavioral dysfunctions associated with dietary iron overload. Physiology & Behavior,1996,59(2):213-219.
[17]Rouault TA.Systemic iron metabolism:a review and implications for brain iron metabolism.Pediatr Neurol,2001,25(2):130-137.
[18]D. Allan B, Christopher M. Lauderback. Lipid peroxidation and protein oxidation in Alzheimer's disease brain:potential causes and consequences involving amyloid P-peptide-associated free radical oxidative stress. Free Radical Biology and Medicine, 2002,32(11):1050-1060.
[19]Stuart T, Brian J.T, Omar M.A.E,et al. New evidence that the Alzheimer β-amyloid peptide does not spontaneously form free radicals:An ESR study using a series of spin-traps. Free Radical Biology and Medicine,2001,30 (10):1154-1162.
[20]Dmitriy F, Jerrel L.Y. Dendritic Ca2+ signalling due to activation ofα 7-containing nicotinic acetylcholine receptors in rat hippocampal neurons. Physiol,2007,582(2):597-611.
[21]Shen ZX. Medical Hypotheses. Brain cholinesterases:Ⅱ. The molecular and cellular basis of Alzheimer's disease. Medical Hypotheses,2004,63(2):308-321.
[22]George T.G, Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:Getting On and Staying On. Current Therapeutic Research,2003,64(4):216-235.
[23]Yu.V.L, Orlovsky M.A., Lushuikova I.V., et al. Neurodegenerative Changes in the Hippocampus within the Early Period of Experimental Diabetes Mellitus. Neurophysiology, 2008,40(1):30-37.
[24]Cai ZY, Yan Y, Zhang J, et al. Cogn itive function and expression of GFAP, IL-1β, TNF-a and Aβ in hippocampal tissues of diabetic rats. Journal of Shanghai Jiao tong University (Medical Science),2009,29(2):130-134.
[25]Martins IJ, Hone E, Foster JK, et al. Apolipoprotein E, cholesterolmetabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry,2006,11 (8):721-736.
[26]Biessels GJ, Kappelle LJ. Increased risk of Alzheimer's disease in Type II diabetes:insulin resistance of the brain or insulin-induced amyloid pathology. Biochem Soc Trans,2005,33 (5):1041 -1044.
[27]Lester-Coll N, Rivera EJ, Soscia SJ, et al. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis,2006,9 (1):13-33.
[28]Nataniel Lester-Coll, Enrique J. Rivera, Stephanie J. Soscia, et al. Intracerebral streptozotocin model of type 3 diabetes:Relevance to sporadic Alzheimer's disease. Journal of Alzheimer's Disease,2006,9(1):13-33.
[29]武月萍,田金洲.胰岛素抵抗与阿尔茨海默病.中国老年学杂志,2005,25(3)：348-350.
[30]Li L, Christian H. Common pathological processes in Alzheimer disease and type 2 diabetes: A review. Brain research review,2007,56(2):384-402.
[31]Jesus A, Felix H.GSK-3 inhititors for Alzheimer's diease. Neurotherapeutics, 2007,7(11):1527-1533.
[32]Felix H, Jesus A. The role of glycogen synthase kinase 3 in the early stages of Alzheimer's disease. FEBS Letters,2008,582(28):3848-3854.
[33]Haan MN. Therapy Insight:type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease.Nat Clin Pract Neurol,2006,2(1):159-166.
[34]Leisson CL, RoccaWA, Hanson VA, et al. Risk of dementia among persons with diabetes mellitus:a population-based cohort study. Am J Epidemiol,1997,145 (4):301-308.
[35]Jose A.L, Tang MX, Yaakov S, et al. Diabetes Mellitus and Risk of Alzheimer's Disease and Dementia with Stroke in a Multiethnic Cohort. American Journal of Epidemiology, 2001,154 (7):635-641.
[36]Ott A, Stolk RP, van Harskamp F, et al. Diabetes mellitus and the risk of dementia:The Rotterdam Study. Neurology,1999,53:1937.
[37]Wang YP, Liu LB. Protection of glucagon-like peptide-1 on pancreatic β-cells. Intern J Endocrinol Metab,2007,27(2):98-100.
[38]Perry T, Haughey NJ, Mattson MP, et al. Protection and reversalof excitotoxic neuronal damage by glucagon-like pep tide-1 and exendin-4. J Pharm acol Exp Ther,2002,302 (3):881-892.
[39]Pedersen WA, Wan R, Zhang P, et al. Urocortin, but not uro-cortinⅡ, protects cultured hippocampal neurons from oxidative and excitotoxic cell death via corticotrop in-releasing hormone recep tor type I. J Neuroscience,2002,22(2):404-412.
[40]刘瑞,胡仁明,王庆华.GLP-1类似物：糖尿病预防和治疗的新型药物.中国糖尿病杂志,2008,16(8)：509-511.
[41]Perry T, Lahiri DK, Sambamurti K, et al. Glucagon-like pep tide-1 decreases endogenous amyloid-beta pep tide (Abeta) levels andp rotects hippocampal neurons from death induced by Abeta and iron. J Neuroscience Research,2003,2(5):603-612.
[42]Perry T, Greig NH. The glucagon-like pep tides:a double-edgedtherapeutic sword. Trends Pharm acol Sci,2003,24 (7):377-383.
[43]Subhas CB, Jean B, Lloyd A.Greene. Glucagon-like Peptide-1 (GLP-1) Diminishes Neuronal Degeneration and Death Caused by NGF Deprivation by Suppressing Bim Induction. Neurochem Research,2008,33(9):1845-1851.
[44]Qin ZX, Sun ZW, Huang J. Mutated recombinant human glucagon-like peptide-1 protects SH-SY5Y cells from apoptosis induced by amyloid- β peptide (1-42). Neuroscience Letters,2008,444(3):217-221.
[45]Victor AG, Christian H. GLP-1 agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. European Journal of Pharmacology, 2008,587(1-3):112-117.
[2]Fatma KD, Belgin SD, Melek O. Protective effects of a calcium channel blocker on apoptosis in thymus of neonatal STZ-diabetic rats. Acta histochemica,2005,107(3):207-214.
[3]Rahul A, Ethika T, Rakesh S, etc. A study of brain insulin receptors, AChE activity and oxidative stress in rat model of ICV STZ induced dementia. Neuropharmacology,2009,56(4): 779-787.
[4]D.K. Arulmozhia, B. Portha. GLP-1 based therapy for type 2 diabetes. European Journal Of Pharmaceutical Sciences,2006,28(1-2):96-108.
[5]Subhas CB, Jean B, Lloyd AG. Glucagon-like Peptide-1 (GLP-1) Diminishes Neuronal Degeneration and Death Caused by NGF Deprivation by Suppressing Bim Induction. Neurochem Research,2008,33(9):1845-1851.
[6]Qin ZX, Sun ZW, Huang J. Mutated recombinant human glucagon-like peptide-1 protects SH-SY5Y cells from apoptosis induced by amyloid-β peptide (1-42). Neuroscience Letters, 2008,444(3):217-221.
[7]Victor A.G, Christian H. GLP-1 agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. European Journal of Pharmacology,2008,587 (1-3):112-117.
[8]诸葛启钏.大鼠脑立体定位图谱.(第三版).北京：人民卫生出版社,2005：图10-图36.
[9]Takashi I, Manabu S, Kazuma K, et al. The influences of juvenile diabetes on memory and hippocampal plasticity in rats:Improving effects of glucagon-like peptide-1. Neuroscience Research,2009,64 (1):67-74.
[10]Natalia S, Yan J, Eliezer G,et al. NAP protects memory, increases soluble tau and reduces tau hyperphosphorylation in a tauopathy model. Neurobiology of Disease,2009,34(2):381-388.
[11]Jesus A.Tau phosphorylation and aggregation in Alzheimer's disease pathology. FEBS Letters,2006,580(12):2922-2927.
[12]胡镜清,温泽淮,赖世隆.Morris水迷宫检测的记忆属性与方法学初探.广州中医药大学学报,2000,17(2)：117-119.
[13]朱大年,吴博威,樊小力,等.生理学(第七版).北京：人民卫生出版社,2008,327-329.
[14]Martins IJ, Hone E, Foster JK, et al. Apolipoprotein E, cholesterolmetabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry,2006,11 (8):721-736.
[15]Biessels GJ, Kappelle LJ. Increased risk of Alzheimer's disease in Type II diabetes:insulin resistance of the brain or insulin-induced amyloid pathology. Biochem Soc Trans,2005,33 (5):1041-1044.
[16]Lester-Coll N, Rivera EJ, Soscia SJ, et al. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis,2006,9 (1):13-33.
[17]曾望远,董克礼.AD的病因机制研究概况.湖南中医杂志,2006,22(1)：77-80.
[18]M.A. Orlovsky, F.Spiga, Y.V.Lebed, et al. Early Molecular Events in the Hippocampus of Rats with Streptozotocin-Induced Diabetes. Neurophsiology,2007,39(6):498-502.
[19]Nataniel L, Enrique J.R, Stephanie J.S, et al. Intracerebral streptozotocin model of type 3 diabetes:Relevance to sporadic Alzheimer's disease. Journal of Alzheimer's Disease,2006, 9(1):13-33.
[20]Rudi DH, Peter P.D. Applications of the Morris water maze in the study of learning and memory. Brain Research Reviews,2001,36(1):60-90.
[1]Butterfield DA, Reed T, Newman SF,et al. Roles of amyloid β-pep-tide-associated oxidative stress and brain p rotein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Free Radical Biology&Medicine,2007,43(5):658-677.
[2]侯佳宁,胡雅儿.阿尔茨海默病淀粉样肽级联假说及其相关基因研究进展[J].神经解剖学杂志,2009,25(1)：111-114.
[3]张婧.早发性痴呆相关基因的研究.实用医学杂志,2008,24(21)：3781-3783.
[4]Yu ZF, Cheng GJ, Hu BR. Mechamism of coloicine impairment on learning and memory, and protective effect of CGP36742 in mice. Brain Research,1997,750 (1):53-59.
[5]曾望远,董克礼.AD的病因机制研究概况.湖南中医杂志,2006,22(1)：77-80.
[6]Liu R, Wang JZ. Protein phosphatase-2A in Alzheimer's disease. Pathophysiolog,2009,16 (4):273-277.
[7]Drewes, G., Ebneth, A. and Mandelkow, E.M. MAPs,MARKs and microtubule dynamics.Trends in Biochemical Science,1998,23 (80);307-311.
[8]Liu T, Li Y. Cholesterol in the pathogenesis of Alzheiner's disease. International Journal of Pathology and Clinical Medicine,2008,28(1):81-84.
[9]朱洪山.脂质代谢在阿尔茨海默病发病机制中的研究进展.重庆医学,2009,38(3)：347-350.
[10]Xie CL, Lund EG, Stephen D, et al. Quantitation of two pathyways for cholesterol excretion from the brain normal mice and mice with neurodegeneration. Journal of Lipid Research, 2003,44(9):1780-1789.
[11]Oddo S, Vasilevko V, Caccamo A, et al. Reduction of soluble Aβ and Tau, but not soluble Aβ alone, ameliorates cognitive decline in transgenic mice with p laques and tangles. J Biol Chem,2006,281(51):39413-39423.
[12]Burn M, Duff K. Cholesterol in Alzheimer's disease and tauopathy. Ann NY Acad Sci, 2002,977(6):367-375.
[13]Distl R, Meske V, Ohm TG. Tangle2bearing neurons contain more free cholesterol than adjacent tangle2free neurons. Acta Neuropathol,2001,101(6):547-554.
[14]Antero S, Johanna O, Anu K, et al. Inflammation in Alzheimer's disease: Amyloid-βoligomers trigger innate immunity defence via pattern recognition receptors. Progress in Neurobiology,2009,87(3):181 - 194.
[15]Angela R.K, Ronald G.C, Ananda P.D, et al. Inflammation and Alzheimer's disease: Possible role of periodontal diseases. Alzheimer's and Dementia,2008,4(4)242-250.
[16]Sobotka T.J, Whittaker P, Sobotka J.M, et al. Neurobehavioral dysfunctions associated with dietary iron overload. Physiology & Behavior,1996,59(2):213-219.
[17]Rouault TA.Systemic iron metabolism:a review and implications for brain iron metabolism.Pediatr Neurol,2001,25(2):130-137.
[18]D. Allan B, Christopher M. Lauderback. Lipid peroxidation and protein oxidation in Alzheimer's disease brain:potential causes and consequences involving amyloid P-peptide-associated free radical oxidative stress. Free Radical Biology and Medicine, 2002,32(11):1050-1060.
[19]Stuart T, Brian J.T, Omar M.A.E,et al. New evidence that the Alzheimer β-amyloid peptide does not spontaneously form free radicals:An ESR study using a series of spin-traps. Free Radical Biology and Medicine,2001,30 (10):1154-1162.
[20]Dmitriy F, Jerrel L.Y. Dendritic Ca2+ signalling due to activation ofα 7-containing nicotinic acetylcholine receptors in rat hippocampal neurons. Physiol,2007,582(2):597-611.
[21]Shen ZX. Medical Hypotheses. Brain cholinesterases:Ⅱ. The molecular and cellular basis of Alzheimer's disease. Medical Hypotheses,2004,63(2):308-321.
[22]George T.G, Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:Getting On and Staying On. Current Therapeutic Research,2003,64(4):216-235.
[23]Yu.V.L, Orlovsky M.A., Lushuikova I.V., et al. Neurodegenerative Changes in the Hippocampus within the Early Period of Experimental Diabetes Mellitus. Neurophysiology, 2008,40(1):30-37.
[24]Cai ZY, Yan Y, Zhang J, et al. Cogn itive function and expression of GFAP, IL-1β, TNF-a and Aβ in hippocampal tissues of diabetic rats. Journal of Shanghai Jiao tong University (Medical Science),2009,29(2):130-134.
[25]Martins IJ, Hone E, Foster JK, et al. Apolipoprotein E, cholesterolmetabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry,2006,11 (8):721-736.
[26]Biessels GJ, Kappelle LJ. Increased risk of Alzheimer's disease in Type II diabetes:insulin resistance of the brain or insulin-induced amyloid pathology. Biochem Soc Trans,2005,33 (5):1041 -1044.
[27]Lester-Coll N, Rivera EJ, Soscia SJ, et al. Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer's disease. J Alzheimers Dis,2006,9 (1):13-33.
[28]Nataniel Lester-Coll, Enrique J. Rivera, Stephanie J. Soscia, et al. Intracerebral streptozotocin model of type 3 diabetes:Relevance to sporadic Alzheimer's disease. Journal of Alzheimer's Disease,2006,9(1):13-33.
[29]武月萍,田金洲.胰岛素抵抗与阿尔茨海默病.中国老年学杂志,2005,25(3)：348-350.
[30]Li L, Christian H. Common pathological processes in Alzheimer disease and type 2 diabetes: A review. Brain research review,2007,56(2):384-402.
[31]Jesus A, Felix H.GSK-3 inhititors for Alzheimer's diease. Neurotherapeutics, 2007,7(11):1527-1533.
[32]Felix H, Jesus A. The role of glycogen synthase kinase 3 in the early stages of Alzheimer's disease. FEBS Letters,2008,582(28):3848-3854.
[33]Haan MN. Therapy Insight:type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease.Nat Clin Pract Neurol,2006,2(1):159-166.
[34]Leisson CL, RoccaWA, Hanson VA, et al. Risk of dementia among persons with diabetes mellitus:a population-based cohort study. Am J Epidemiol,1997,145 (4):301-308.
[35]Jose A.L, Tang MX, Yaakov S, et al. Diabetes Mellitus and Risk of Alzheimer's Disease and Dementia with Stroke in a Multiethnic Cohort. American Journal of Epidemiology, 2001,154 (7):635-641.
[36]Ott A, Stolk RP, van Harskamp F, et al. Diabetes mellitus and the risk of dementia:The Rotterdam Study. Neurology,1999,53:1937.
[37]Wang YP, Liu LB. Protection of glucagon-like peptide-1 on pancreatic β-cells. Intern J Endocrinol Metab,2007,27(2):98-100.
[38]Perry T, Haughey NJ, Mattson MP, et al. Protection and reversalof excitotoxic neuronal damage by glucagon-like pep tide-1 and exendin-4. J Pharm acol Exp Ther,2002,302 (3):881-892.
[39]Pedersen WA, Wan R, Zhang P, et al. Urocortin, but not uro-cortinⅡ, protects cultured hippocampal neurons from oxidative and excitotoxic cell death via corticotrop in-releasing hormone recep tor type I. J Neuroscience,2002,22(2):404-412.
[40]刘瑞,胡仁明,王庆华.GLP-1类似物：糖尿病预防和治疗的新型药物.中国糖尿病杂志,2008,16(8)：509-511.
[41]Perry T, Lahiri DK, Sambamurti K, et al. Glucagon-like pep tide-1 decreases endogenous amyloid-beta pep tide (Abeta) levels andp rotects hippocampal neurons from death induced by Abeta and iron. J Neuroscience Research,2003,2(5):603-612.
[42]Perry T, Greig NH. The glucagon-like pep tides:a double-edgedtherapeutic sword. Trends Pharm acol Sci,2003,24 (7):377-383.
[43]Subhas CB, Jean B, Lloyd A.Greene. Glucagon-like Peptide-1 (GLP-1) Diminishes Neuronal Degeneration and Death Caused by NGF Deprivation by Suppressing Bim Induction. Neurochem Research,2008,33(9):1845-1851.
[44]Qin ZX, Sun ZW, Huang J. Mutated recombinant human glucagon-like peptide-1 protects SH-SY5Y cells from apoptosis induced by amyloid- β peptide (1-42). Neuroscience Letters,2008,444(3):217-221.
[45]Victor AG, Christian H. GLP-1 agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. European Journal of Pharmacology, 2008,587(1-3):112-117.