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Author: 涂榕萱
Tu, Rong-Syuan
Thesis Title: α-硫辛酸緩解高脂飲食及STZ誘發第二型糖尿病大鼠認知功能損傷之探討
Alleviative effect of alpha-lipoic acid on cognition impairment in type 2 diabetic rats induced by high-fat diet plus streptozotocin
Advisor: 沈賜川
Shen, Szu-Chuan
吳瑞碧
Wu, Swi-Bea
丁俞文
Ting, Yu-Wen
Degree: 碩士
Master
Department: 人類發展與家庭學系
Department of Human Development and Family Studies
Thesis Publication Year: 2018
Academic Year: 106
Language: 中文
Number of pages: 83
Keywords (in Chinese): 第二型糖尿病阿茲海默症腦部胰島素阻抗長期增益效應
Keywords (in English): Type 2 diabetes, Alzheimer's disease, cerebral insulin signaling, long-term potentiation
DOI URL: http://doi.org/10.6345/THE.NTNU.DHDFS.025.2018.A06
Thesis Type: Academic thesis/ dissertation
Reference times: Clicks: 193Downloads: 3
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  • 近年來臨床和流行病學研究發現,第二型糖尿病(T2DM)與阿茲海默症(AD)的發展有很高的相關性,有研究指出胰島素可參與AD相關蛋白如β-澱粉樣蛋白(Aβ)之調節。α-硫辛酸(ALA)已被證實可以改善糖尿病大鼠的胰島素阻抗。本研究探討ALA改善高脂飲食(HFD)及鏈脲佐菌素(STZ)誘導的糖尿病大鼠認知障礙、腦胰島素抵抗及突觸可塑性異常的效果。Wistar雄性大鼠給予HFD (60%脂肪卡路里) 4週後,以腹腔注射(ip) STZ (30mg/kg體重)誘發糖尿病。糖尿病大鼠每日管餵ALA 13週後,進行被動迴避試驗及Morris水迷宮試驗以評估大鼠認知功能。大鼠犧牲後採集血液及腦組織分析,並以Western blotting檢測海馬迴和皮質的胰島素訊息路徑、長期增益效應(LTP)及突觸可塑性相關蛋白的表現。被動迴避試驗與Morris水迷宮試驗結果顯示,給予ALA處理能顯著改善HFD/STZ誘導的糖尿病大鼠的認知功能障礙(p<0.05)。Western blotting分析結果顯示,給予ALA處理能顯著改善糖尿病大鼠海馬迴與皮質的突觸可塑性相關蛋白以及胰島素訊號傳導相關蛋白之表現(p<0.05)。在本研究結果發現,ALA可經由緩解糖尿病大鼠腦部胰島素阻抗來改善大腦神經突觸的可塑性及認知功能。目前ALA已是市面上的保健食品,希望可透過此研究讓ALA在未來也能作為阿茲海默症疾病的輔助用藥。

    Recently, clinical and epidemiological studies suggest that T2DM is strongly interrelated with Alzheimer's disease (AD), and proposed that insulin involved in the modulation of AD-related proteins such as β-Amyloid (Aβ). Studies also reported that α-lipoic acid (ALA) improved insulin resistance in diabetic rats. This study examines the ameliorative effect of ALA on cognition impairment, cerebral insulin resistance and synaptic plasticity abnormality in high-fat diet (HFD) plus streptozotocin (STZ) induced diabetic rats. Male Wistar rats fed HFD (60% fat of calorie) for 4 weeks were intraperitoneally (ip) injected STZ (30mg/kg b.w.) to induce diabetes. The diabetic rats were orally administered with ALA once a day for 13 weeks. Passive avoidance test and Morris water maze test was performed to assess cognitive ability of rats. The blood and brain specimens were collected for biochemical analysis after the rats were sacrificed. Western blotting was used to determine the protein expressions of hippocampal and cortex insulin signaling pathway, long-term potentiation and synaptic plasticity-related proteins expression. The result from the passive avoidance test and Morris Water Maze test shows that the administration of ALA significantly improved the cognitive impairment in HFD/STZ-induced diabetic rats (p<0.05). Western blotting analysis indicates the expression of cerebral, including hippocampal and cortex, synaptic plasticity-related protein, and cerebral insulin signaling-related protein significantly increased in ALA-treated diabetic rats (p<0.05). The findings in this study suggest that ALA may ameliorate cognition impairment via improving cerebral synaptic plasticity and alleviating cerebral insulin resistance in diabetic rats.

    第一章 前言 1 第二章 文獻回顧 2 第一節 阿茲海默症(Alzheimer’s disease, AD) 2 一、阿茲海默症流行病學 2 二、阿茲海默症的致病機轉 3 1.β類澱粉樣蛋白假說 (β-Amyloid hypothesis) 4 2.Tau蛋白假說 (Tau hypothesis) 6 3.長期增益效應 (Long-term potentiation, LTP) 7 三、阿茲海默症的疾病階段 9 1.輕度阿茲海默症(Mild Alzheimer's disease, early-stage) 9 2.中度阿茲海默症(Moderate Alzheimer's disease, middle-stage) 9 3.重度阿茲海默症(Severe Alzheimer's disease, late-stage) 10 四、阿茲海默症的診斷方法 10 五、阿茲海默症的治療方法 12 1.藥物治療 12 2.非藥物治療 12 第二節 糖尿病(Diabetes Mellitus, DM) 14 一、糖尿病流行病學 14 二、糖尿病的疾病分類 15 1.糖尿病前症 (Prediabetes) 15 2.第一型糖尿病 (Type 1 Diabetes Mellitus, T1DM) 15 3.第二型糖尿病 (Type 2 Diabetes Mellitus, T2DM) 15 4.妊娠糖尿病 (Gestational diabetes, GDM) 16 三、診斷方式 16 1.糖尿病高風險群的分類 17 2.糖尿病診斷標準 17 3.第一型和第二型糖尿病的鑑別診斷 18 第三節 阿茲海默症與糖尿病 19 一、大腦與胰島素訊息傳遞的關係 19 二、糖尿病對腦內β-Amyloid清除的影響 20 三、胰島素阻抗與過度磷酸化的Tau蛋白 22 第四節 硫辛酸(alpha-lipoic acid, ALA) 23 第三章 研究動機與目的及實驗架構 24 第一節 研究動機與目的 24 第二節 實驗架構 25 第四章 實驗材料與方法 26 第一節 實驗材料 26 一、實驗樣品來源 26 二、實驗動物來源 26 三、實驗動物飼料來源 26 四、實驗藥品及試劑 26 第二節 實驗步驟與方法 30 一、實驗動物飼養、誘導及分組 30 二、試驗方法 31 第五章 結果與討論 41 第一節 α-硫辛酸對HFD/STZ誘導T2DM大鼠腦組織重量及血清胰島素之影響 41 第二節 α-硫辛酸對HFD/STZ誘導T2DM大鼠認知功能之影響 44 一、被動迴避試驗 44 二、Morris水迷宮 46 1.空間探索試驗 (Spatial acquisition of Morris Water Maze) 46 2.探測試驗 (Probe trial of Morris Water Maze) 46 3.生理功能測試 47 第三節 α-硫辛酸對HFD/STZ誘導T2DM大鼠大腦蛋白質表現之影響 51 一、α-硫辛酸對T2DM大鼠大腦海馬迴與皮質之胰島素訊息路經及Tau蛋白磷酸化路徑相關蛋白質表現之影響 51 二、α-硫辛酸對T2DM大鼠大腦海馬迴與皮質胰島素降解酶蛋白質表現之影響 59 三、α-硫辛酸對T2DM大鼠大腦海馬迴與皮質長期增益效應路徑蛋白質表現之影響 61 四、α-硫辛酸對T2DM大鼠大腦海馬迴與皮質神經突觸可塑性相關蛋白質表現之影響 69 第六章 結論 73 第七章 附錄 75 第八章 參考文獻 76

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