臺灣博碩士論文加值系統

　　第二型糖尿病與阿茲海默症影響國人健康甚鉅，許多研究結果顯示第二型糖尿病是阿茲海默症疾病的高危險因子，但其詳細機轉仍不清楚。本研究旨在釐清第二型糖尿病小鼠學習與記憶是否受損，以及腦中Tau蛋白是否有過度磷酸化現象，同時以雙螢光素酶報導基因平台篩選潛力藥物。首先，我們檢測野生型 (WT)、異合子 (db/+)、第二型糖尿病 (db/db) 小鼠的體重、一般血糖值與禁食後血糖值。結果顯示，db/db小鼠的體重及血糖值均較db/+及WT小鼠顯著增加。水迷津訓練結果顯示，db/db小鼠直至訓練第五天仍無法找到平台；探針實驗結果亦顯示，db/db小鼠在原來平台所在象限的停留時間百分比只有12%，顯著低於WT與db/+小鼠；db/db小鼠經過平台的次數也顯著低於WT與db/+小鼠，證實db/db小鼠的空間學習與記憶嚴重受損。我們接著以西方墨點法分析小鼠腦部海馬迴組織的Tau蛋白磷酸化程度，db/db小鼠海馬迴中Tau蛋白的Thr205、Ser262、Ser396磷酸化程度確實顯著增加，或許db/db小鼠空間學習及記憶能力較差，可能與Tau蛋白過度磷酸化有關。此外，本論文利用雙螢光素酶報導基因平台篩選潛力藥物，我們已找到能顯著促進PPRE媒介的報導基因表現之潛力藥物，並且釐清此藥物所活化的下游訊息傳遞路徑。至於此藥物是否能改善db/db小鼠的記憶缺損、Tau蛋白過度磷酸化及高血糖等現象尚有待證實。

　　Type 2 diabetes mellitus and Alzheimer's disease (AD) affect the health of citizens hugely. A large body of evidence indicates that diabetic patients have an increased risk of developing AD; however, the mechanism is unknown. This study is aimed to clarify whether diabetic mice show impaired memory or hyperphosphorylation of Tau in their brains. We also screen potential drugs by dual-luciferase reporter assay for therapy. First, we analyzed the body weight, normal blood glucose levels and fasting blood glucose levels of wild-type (WT), heterozygous (db/+), and type 2 diabetes (db/db) mice. The results showed that the body weight and blood glucose levels of db/db mice increased significantly when compared with db/+ and WT mice. Next, water maze was carried out to examine the spatial memory formation of db/db mice. The result revealed that db/db mice did not find the platform till the end of training. One day later, the probe trial test was carried out. It showed that db/db mice spent only 12% of time in the target quadrant than did the WT and db/+ mice. It also showed that db/db mice reached the platform fewer times than WT and db/+ mice. The results demonstrated that the spatial memory formation is severely impaired in db/db mice. The mouse brains were then dissected out and subjected to western blot for Tau phosphorylation analysis. The results showed that Thr205, Ser262, and Ser396 of Tau were highly phosphorylated in db/db mice. This suggests that the memory impairment in db/db mice might be related to the hyperphosphorylation of Tau. In addition, the use of the dual-luciferase reporter gene assay for screening potential drugs was conducted. We have identified a potential drug that drives PPRE-mediated reporter gene expression potently and the underlying signaling pathways was studied by the reporter assay platform as well. Whether this potential drug exerts its protective effect on memory deficit, Tau phosphorylation, or hyperglycemia in db/db mice yet to be further investigated.

目錄
中文摘要 I
英文摘要 II
目錄 III
圖目錄 V
縮寫對照表 VI
第一章、 緒論 1
第一節、 糖尿病 (Diabetes mellitus, DM) 1
第二節、 學習與記憶 7
第三節、 阿茲海默症 (Alzheimer’s disease, AD) 8
第四節、 藥物介紹 11
第五節、 研究目的 13
第六節、 實驗設計 13
第二章、 材料與方法 15
第一節、 動物來源及飼養 15
第二節、 動物基因型鑑定 15
第三節、 血糖檢測 17
第四節、 莫氏水迷津學習實驗（Morris water maze learning test） 17
第五節、 腦組織採樣 17
第六節、 蛋白質萃取 18
第七節、 蛋白質濃度測定 18
第八節、 西方墨點法 (Western blot) 18
第九節、 細胞培養 20
第十節、 藥物製備 20
第十一節、 質體 (Plasmids) 22
第十二節、 小量質體 DNA 製備 22
第十三節、 MTT 細胞存活率分析 23
第十四節、 藥物處理及細胞轉染 23
第十五節、 雙螢光素酶報導基因分析 (Dual-luciferase reporter assay) 24
第十六節、 統計方法 25
第三章、 結果 26
第一節、 以PCR方式進行db/db第二型糖尿病小鼠基因型檢測 26
第二節、 db/db第二型糖尿病小鼠之體重與血糖分析 26
第三節、 以莫氏水迷津檢測db/db第二型糖尿病對小鼠的空間記憶之影響 27
第四節、 使用西方墨點法分析糖尿病對小鼠的海馬迴組織Tau蛋白磷酸化程度之影響 28
第五節、 使用PC12細胞，轉染具有PPRE之報導基因，觀察Harmine與Y314藥物是否能促進報導基因進行轉錄轉譯作用 29
第六節、 Y314不影響PC12細胞存活率 29
第七節、 求得Y314半致效應濃度 (EC50) 30
第八節、 探討Y314影響PPRE媒介的基因表現之可能路徑 30
第四章、 討論 32
第五章、 結論與未來展望 37
第六章、 圖 38
附錄 49
參考文獻 53

中文參考文獻
王智賢、徐邦治、方德昭（2006）。糖尿病腎病變。慈濟醫學，18，25-29。
行政院衛生署（2010）。衛生統計指標。檢自
http://www.doh.gov.tw/CHT2006/DM/DM2_2.aspx?now_fod_list_no=10251&class_no=440&level_no=1。
財團法人糖尿病關懷基金會（2002）。檢自http://www.dmcare.org.tw/。
彭瓊琿、張浤榮、黃建寧（2010）。糖尿病合併末期腎臟病患者之透析選擇--文獻回顧
與流程建議。中山醫學雜誌，21:1，101-114。
張曉婷、杜明勳（2005）。糖尿病神經病變--診斷及處置。基層醫學，20:4，84-88。

西文參考文獻
Alonso, A.D., Di Clerico, J., Li, B., Corbo, C.P., Alaniz, M.E., Grundke-Iqbal, I. and Iqbal, K. (2010). Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration. J Biol Chem 285, 30851-30860.
Awad, N., Gagnon, M. and Messier, C. (2004). The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J Clin Exp Neuropsychol 26, 1044-1080.
Baron, A.D., Zhu, J.S., Zhu, J.H., Weldon, H., Maianu, L. and Garvey, W.T. (1995). Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity. J Clin Invest 96, 2792-2801.
Bellamy, L., Casas, J.P., Hingorani, A.D. and Williams, D. (2009). Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 373, 1773-1779.
Berchtold, N.C. and Cotman, C.W. (1998). Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s. Neurobiol Aging 19, 173-189.
Biernat, J., Gustke, N., Drewes, G., Mandelkow, E.M. and Mandelkow, E. (1993). Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron 11, 153-163.
Biessels, G.J., Kamal, A., Ramakers, G.M., Urban, I.J., Spruijt, B.M., Erkelens, D.W. and Gispen, W.H. (1996). Place learning and hippocampal synaptic plasticity in streptozotocin-induced diabetic rats. Diabetes 45, 1259-1266.
Bramblett, G.T., Goedert, M., Jakes, R., Merrick, S.E., Trojanowski, J.Q. and Lee, V.M. (1993). Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 10, 1089-1099.
Brands, A.M., Biessels, G.J., de Haan, E.H., Kappelle, L.J. and Kessels, R.P. (2005). The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes Care 28, 726-735.
Bulpitt, C.J., Li, Y., Bulpitt, P.F. and Wang, J. (2007). The use of orchids in Chinese medicine. J R Soc Med 100, 558-563.
Carro, E. and Torres-Aleman, I. (2004). The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer's disease. Eur J Pharmacol 490, 127-133.
Chen, H., Charlat, O., Tartaglia, L.A., Woolf, E.A., Weng, X., Ellis, S.J., Lakey, N.D., et al. (1996). Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491-495.
Chen, Y., Jimenez, A.R. and Medh, J.D. (2006). Identification and regulation of novel PPAR-gamma splice variants in human THP-1 macrophages. Biochim Biophys Acta, 13.
Chen, Y.C., Wu, J.S., Tsai, H.D., Huang, C.Y., Chen, J.J., Sun, G.Y. and Lin, T.N. (2012). Peroxisome Proliferator-Activated Receptor Gamma (PPAR-gamma) and Neurodegenerative Disorders. Mol Neurobiol 21, 21.
Chua, S.C., Jr., Chung, W.K., Wu-Peng, X.S., Zhang, Y., Liu, S.M., Tartaglia, L. and Leibel, R.L. (1996). Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271, 994-996.
Clausen, T.D., Mathiesen, E.R., Hansen, T., Pedersen, O., Jensen, D.M., Lauenborg, J. and Damm, P. (2008). High prevalence of type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type 1 diabetes: the role of intrauterine hyperglycemia. Diabetes Care 31, 340-346.
Clodfelder-Miller, B.J., Zmijewska, A.A., Johnson, G.V. and Jope, R.S. (2006). Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency. Diabetes 55, 3320-3325.
Corsetti, J.P., Sparks, J.D., Peterson, R.G., Smith, R.L. and Sparks, C.E. (2000). Effect of dietary fat on the development of non-insulin dependent diabetes mellitus in obese Zucker diabetic fatty male and female rats. Atherosclerosis 148, 231-241.
Craft, S., Dagogo-Jack, S.E., Wiethop, B.V., Murphy, C., Nevins, R.T., Fleischman, S., Rice, V., Newcomer, J.W. and Cryer, P.E. (1993). Effects of hyperglycemia on memory and hormone levels in dementia of the Alzheimer type: a longitudinal study. Behav Neurosci 107, 926-940.
DeKosky, S.T., Scheff, S.W. and Styren, S.D. (1996). Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 5, 417-421.
Desrocher, M. and Rovet, J. (2004). Neurocognitive correlates of type 1 diabetes mellitus in childhood. Child Neuropsychol 10, 36-52.
Dubois, M., Vantyghem, M.C., Schoonjans, K. and Pattou, F. (2002). [Thiazolidinediones in type 2 diabetes. Role of peroxisome proliferator-activated receptor gamma (PPARgamma)]. Ann Endocrinol 63, 511-523.
Elsner, M., Tiedge, M. and Lenzen, S. (2003). Mechanism underlying resistance of human pancreatic beta cells against toxicity of streptozotocin and alloxan. Diabetologia 46, 1713-1714.
Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E.A., Frosch, M.P., Eckman, C.B., et al. (2003). Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 100, 4162-4167.
Forman, B.M., Tontonoz, P., Chen, J., Brun, R.P., Spiegelman, B.M. and Evans, R.M. (1995). 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83, 803-812.
Freude, S., Plum, L., Schnitker, J., Leeser, U., Udelhoven, M., Krone, W., Bruning, J.C. and Schubert, M. (2005). Peripheral hyperinsulinemia promotes tau phosphorylation in vivo. Diabetes 54, 3343-3348.
Frost, D., Meechoovet, B., Wang, T., Gately, S., Giorgetti, M., Shcherbakova, I. and Dunckley, T. (2011). beta-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer's disease-related sites. PLoS One 6.
Furuta, M., Yano, Y., Gabazza, E.C., Araki-Sasaki, R., Tanaka, T., Katsuki, A., Hori, Y., et al. (2002). Troglitazone improves GLUT4 expression in adipose tissue in an animal model of obese type 2 diabetes mellitus. Diabetes Res Clin Pract 56, 159-171.
Fuster-Matanzo, A., Llorens-Martin, M., Jurado-Arjona, J., Avila, J. and Hernandez, F. (2012). Tau Protein and Adult Hippocampal Neurogenesis. Front Neurosci 6, 9.
Gao, X., Li, B., Jiang, H., Liu, F., Xu, D. and Liu, Z. (2007). Dioscorea opposita reverses dexamethasone induced insulin resistance. Fitoterapia 78, 12-15.
Glabe, C.G. (2006). Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol Aging 27, 570-575.
Glaser, N., Anderson, S., Leong, W., Tancredi, D. and O'Donnell, M. (2012). Cognitive dysfunction associated with diabetic ketoacidosis in rats. Neurosci Lett 510, 110-114.
Glaser, N.S., Wootton-Gorges, S.L., Marcin, J.P., Buonocore, M.H., Dicarlo, J., Neely, E.K., Barnes, P., Bottomly, J. and Kuppermann, N. (2004). Mechanism of cerebral edema in children with diabetic ketoacidosis. J Pediatr 145, 164-171.
Goate, A., Chartier-Harlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704-706.
Goldstein, L.B., Adams, R., Becker, K., Furberg, C.D., Gorelick, P.B., Hademenos, G., Hill, M., et al. (2001). Primary prevention of ischemic stroke: A statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke 32, 280-299.
Greenwood, C.E. and Winocur, G. (2005). High-fat diets, insulin resistance and declining cognitive function. Neurobiol Aging 1, 42-45.
Gupta, R. and Gupta, L.K. (2012). Improvement in long term and visuo-spatial memory following chronic pioglitazone in mouse model of Alzheimer's disease. Pharmacol Biochem Behav 102, 184-190.
Hebert, L.E., Scherr, P.A., Bienias, J.L., Bennett, D.A. and Evans, D.A. (2003). Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 60, 1119-1122.
Hebert, R., Lindsay, J., Verreault, R., Rockwood, K., Hill, G. and Dubois, M.F. (2000). Vascular dementia : incidence and risk factors in the Canadian study of health and aging. Stroke 31, 1487-1493.
Himmelstein, D.S., Ward, S.M., Lancia, J.K., Patterson, K.R. and Binder, L.I. (2012). Tau as a therapeutic target in neurodegenerative disease. Pharmacol Ther 10, 10.
Hsieh, M.T., Wu, C.R. and Chen, C.F. (1997). Gastrodin and p-hydroxybenzyl alcohol facilitate memory consolidation and retrieval, but not acquisition, on the passive avoidance task in rats. J Ethnopharmacol 56, 45-54.
Huang, N.K., Lin, J.H., Lin, J.T., Lin, C.I., Liu, E.M., Lin, C.J., Chen, W.P., et al. (2011). A new drug design targeting the adenosinergic system for Huntington's disease. PLoS One 6, 21.
Iacobazzi, V., Convertini, P., Infantino, V., Scarcia, P., Todisco, S. and Palmieri, F. (2009). Statins, fibrates and retinoic acid upregulate mitochondrial acylcarnitine carrier gene expression. Biochem Biophys Res Commun 388, 643-647.
Jolivalt, C.G., Lee, C.A., Beiswenger, K.K., Smith, J.L., Orlov, M., Torrance, M.A. and Masliah, E. (2008). Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer's disease and correction by insulin. J Neurosci Res 86, 3265-3274.
Jovanovic, L. (1998) American Diabetes Association's Fourth International Workshop-Conference on Gestational Diabetes Mellitus: summary and discussion. Therapeutic interventions, Diabetes Care. 1998 Aug;21 Suppl 2:B131-7.
Kajita, K., Ishizuka, T., Miura, A., Kanoh, Y., Ishizawa, M., Kimura, M., Muto, N. and Yasuda, K. (2001). Glucocorticoid-induced insulin resistance associates with activation of protein kinase C isoforms. Cell Signal 13, 169-175.
Kalmijn, S., Feskens, E.J., Launer, L.J., Stijnen, T. and Kromhout, D. (1995). Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men. Diabetologia 38, 1096-1102.
Kim, B., Backus, C., Oh, S., Hayes, J.M. and Feldman, E.L. (2009). Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology 150, 5294-5301.
Kim, D.S., Kim, J.Y. and Han, Y.S. (2007). Alzheimer's disease drug discovery from herbs: neuroprotectivity from beta-amyloid (1-42) insult. J Altern Complement Med 13, 333-340.
Kim, H.J., Lee, S.R. and Moon, K.D. (2003a). Ether fraction of methanol extracts of Gastrodia elata, medicinal herb protects against neuronal cell damage after transient global ischemia in gerbils. Phytother Res 17, 909-912.
Kim, H.J., Moon, K.D., Lee, D.S. and Lee, S.H. (2003b). Ethyl ether fraction of Gastrodia elata Blume protects amyloid beta peptide-induced cell death. J Ethnopharmacol 84, 95-98.
Kim, H.J., Moon, K.D., Oh, S.Y., Kim, S.P. and Lee, S.R. (2001). Ether fraction of methanol extracts of Gastrodia elata, a traditional medicinal herb, protects against kainic acid-induced neuronal damage in the mouse hippocampus. Neurosci Lett 314, 65-68.
Kim, S.T., Kim, J.D., Lyu, Y.S., Lee, M.Y. and Kang, H.W. (2006). Neuroprotective effect of some plant extracts in cultured CT105-induced PC12 cells. Biol Pharm Bull 29, 2021-2024.
Konrad, R.J. and Kudlow, J.E. (2002). The role of O-linked protein glycosylation in beta-cell dysfunction. Int J Mol Med 10, 535-539.
Kroner, Z. (2009). The relationship between Alzheimer's disease and diabetes: Type 3 diabetes? Altern Med Rev 14, 373-379.
Ksiezak-Reding, H., Pyo, H.K., Feinstein, B. and Pasinetti, G.M. (2003). Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. Biochim Biophys Acta 20, 159-168.
Lazennec, G., Canaple, L., Saugy, D. and Wahli, W. (2000). Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators. Mol Endocrinol 14, 1962-1975.
Li, Y.Y., Liu, H.H., Chen, H.L. and Li, Y.P. (2012). Adipose-derived mesenchymal stem cells ameliorate STZ-induced pancreas damage in type 1 diabetes. Biomed Mater Eng 22, 97-103.
Link, A.A., Kino, T., Worth, J.A., McGuire, J.L., Crane, M.L., Chrousos, G.P., Wilder, R.L. and Elenkov, I.J. (2000). Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. J Immunol 164, 436-442.
Lo, H.C., Tu, S.T., Lin, K.C. and Lin, S.C. (2004). The anti-hyperglycemic activity of the fruiting body of Cordyceps in diabetic rats induced by nicotinamide and streptozotocin. Life Sci 74, 2897-2908.
Loe, H. (1993). Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 16, 329-334.
Luo, J., Quan, J., Tsai, J., Hobensack, C.K., Sullivan, C., Hector, R. and Reaven, G.M. (1998). Nongenetic mouse models of non-insulin-dependent diabetes mellitus. Metabolism 47, 663-668.
Martin, S.J. and Clark, R.E. (2007). The rodent hippocampus and spatial memory: from synapses to systems. Cell Mol Life Sci 64, 401-431.
Martins, I.J., Hone, E., Foster, J.K., Sunram-Lea, S.I., Gnjec, A., Fuller, S.J., Nolan, D., Gandy, S.E. and Martins, R.N. (2006). Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry 11, 721-736.
Masiello, P., Broca, C., Gross, R., Roye, M., Manteghetti, M., Hillaire-Buys, D., Novelli, M. and Ribes, G. (1998). Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes 47, 224-229.
McCrimmon, R.J., Ryan, C.M. and Frier, B.M. (2012). Diabetes and cognitive dysfunction. Lancet 379, 2291-2299.
Mishra, M., Huang, J., Lee, Y.Y., Chua, D.S., Lin, X., Hu, J.M. and Heese, K. (2011). Gastrodia elata modulates amyloid precursor protein cleavage and cognitive functions in mice. Biosci Trends 5, 129-138.
Morris, R.G., Garrud, P., Rawlins, J.N. and O'Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature 297, 681-683.
Moura, D.J., Rorig, C., Vieira, D.L., Henriques, J.A., Roesler, R., Saffi, J. and Boeira, J.M. (2006). Effects of beta-carboline alkaloids on the object recognition task in mice. Life Sci 79, 2099-2104.
Mucke, L., Masliah, E., Yu, G.Q., Mallory, M., Rockenstein, E.M., Tatsuno, G., Hu, K., et al. (2000). High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20, 4050-4058.
Okamoto, S., Pouladi, M.A., Talantova, M., Yao, D., Xia, P., Ehrnhoefer, D.E., Zaidi, R., et al. (2009). Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 15, 1407-1413.
Ott, A., Stolk, R.P., van Harskamp, F., Pols, H.A., Hofman, A. and Breteler, M.M. (1999). Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53, 1937-1942.
Planel, E., Tatebayashi, Y., Miyasaka, T., Liu, L., Wang, L., Herman, M., Yu, W.H., et al. (2007). Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci 27, 13635-13648.
Qi, C., Zhu, Y. and Reddy, J.K. (2000). Peroxisome proliferator-activated receptors, coactivators, and downstream targets. Cell Biochem Biophys 32, 187-204.
Reed, M.J., Meszaros, K., Entes, L.J., Claypool, M.D., Pinkett, J.G., Gadbois, T.M. and Reaven, G.M. (2000). A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 49, 1390-1394.
Rissman, R.A., Poon, W.W., Blurton-Jones, M., Oddo, S., Torp, R., Vitek, M.P., LaFerla, F.M., Rohn, T.T. and Cotman, C.W. (2004). Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114, 121-130.
Ryan, C.M. and Geckle, M.O. (2000). Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes. Diabetes Care 23, 1486-1493.
Sato, T., Magata, K., Koga, N. and Mitsumoto, Y. (1998). Defect of an early event of glucose metabolism in skeletal muscle of the male Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a non-insulin-dependent diabetes mellitus (NIDDM) model. Biochem Biophys Res Commun 245, 378-381.
Schneider, A., Biernat, J., von Bergen, M., Mandelkow, E. and Mandelkow, E.M. (1999). Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38, 3549-3558.
Scoville, W.B. and Milner, B. (1957). Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 20, 11-21.
Sengupta, A., Kabat, J., Novak, M., Wu, Q., Grundke-Iqbal, I. and Iqbal, K. (1998). Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys 357, 299-309.
Sharma, B. and Singh, N. (2011). Behavioral and biochemical investigations to explore pharmacological potential of PPAR-gamma agonists in vascular dementia of diabetic rats. Pharmacol Biochem Behav 100, 320-329.
Sima, A.A., Zhang, W., Xu, G., Sugimoto, K., Guberski, D. and Yorek, M.A. (2000). A comparison of diabetic polyneuropathy in type II diabetic BBZDR/Wor rats and in type I diabetic BB/Wor rats. Diabetologia 43, 786-793.
Stevens, M.J., Obrosova, I., Pop-Busui, R., Greene, D.A. and Feldman, E.L. (2002). Pathogenesis of Diabetic Neuorpathy. In: Porte Jr D, Sherwin RS, Baron A, eds. Ellenberg and Rifkin's diabetes mellitus. Philadelphia: McGraw Hill, 747-770.
Stolk, R.P., Breteler, M.M., Ott, A., Pols, H.A., Lamberts, S.W., Grobbee, D.E. and Hofman, A. (1997). Insulin and cognitive function in an elderly population. The Rotterdam Study. Diabetes Care 20, 792-795.
Strachan, M.W., Deary, I.J., Ewing, F.M. and Frier, B.M. (1997). Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies. Diabetes Care 20, 438-445.
Stummvoll, G.H., Aringer, M., Smolen, J.S., Schmaldienst, S., Jimenez-Boj, E., Horl, W.H., Graninger, W.B. and Derfler, K. (2005). IgG immunoadsorption reduces systemic lupus erythematosus activity and proteinuria: a long term observational study. Ann Rheum Dis 64, 1015-1021.
van den Berg, E., Kloppenborg, R.P., Kessels, R.P., Kappelle, L.J. and Biessels, G.J. (2009). Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: A systematic comparison of their impact on cognition. Biochim Biophys Acta 5, 470-481.
Waki, H., Park, K.W., Mitro, N., Pei, L., Damoiseaux, R., Wilpitz, D.C., Reue, K., Saez, E. and Tontonoz, P. (2007). The small molecule harmine is an antidiabetic cell-type-specific regulator of PPARgamma expression. Cell Metab 5, 357-370.
Watson, G.S. and Craft, S. (2003). The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs 17, 27-45.
Xiang, G.Q., Tang, S.S., Jiang, L.Y., Hong, H., Li, Q., Wang, C., Wang, X.Y., Zhang, T.T. and Yin, L. (2012). PPARgamma agonist pioglitazone improves scopolamine-induced memory impairment in mice. J Pharm Pharmacol 64, 589-596.
Yang, G.K., Fredholm, B.B., Kieffer, T.J. and Kwok, Y.N. (2012). Improved blood glucose disposal and altered insulin secretion patterns in adenosine A1 receptor knockout mice. Am J Physiol Endocrinol Metab 303, 1.
Young, A.B. and Fagg, G.E. (1990). Excitatory amino acid receptors in the brain: membrane binding and receptor autoradiographic approaches. Trends Pharmacol Sci 11, 126-133.