臺灣博碩士論文加值系統

本研究利用J20轉基因小鼠作為阿茲海默症 (J20 AD) 模式動物，並以低、中、高劑量豌豆蛋白水解物 (Pea protein hydrolysate, PPH) 餵食八週，分別為200、600、1000 mg/kg鼠/day，探討PPH對於J20 AD模式鼠之體重與組織相對重量、血清生化指數、認知行為能力及AD相關病理特徵之影響。結果顯示各組小鼠在體重及臟器相對重量上並無顯著差異，在各項血清生化指標中，同樣觀察到各組小鼠間並無異常情形，表明餵食PPH八週並不會對小鼠造成健康上的影響；其次，J20 AD模式鼠在認知行為能力上，經由餵食PPH後進行水迷宮實驗 (Morris water maze)證實，中劑量組具有改善學習記憶能力的趨勢；另外在曠野試驗 (Open field, OP )中，經餵食PPH的三個組別均顯著降低J20 AD模式鼠的移動距離及提升其在中間區塊停留時間的趨勢，表明PPH具降低J20 AD小鼠焦慮之潛力；在J20 AD模式鼠海馬迴中，Aβ 40與Aβ 42濃度雖然與WT小鼠無顯著差異，但經由餵食PPH後，與未處理的J20 AD模式鼠組相比，高劑量PPH組顯著降低Aβ 40濃度 (p < 0.05)，另外在Aβ 42濃度上，中、高劑量PPH組與未處理的J20 AD模式鼠組相比，均顯著降低Aβ 42濃度 (p < 0.05)，上述Aβ濃度與海馬迴澱粉樣斑塊切片圖對照，可以觀察到經餵食PPH的低、中及高劑量組，其Aβ斑塊陽性表現量有下降的趨勢；在β-secretase濃度上，未處理的J20 AD模式鼠組皆有高於WT組的趨勢，但彼此間無顯著差異，其中高劑量PPH組與未處理的J20 AD模式鼠組相比，顯著降低其β-secretase濃度 (p < 0.05)；此外在Caspase 3濃度上，未處理的J20 AD模式鼠組顯著高於WT組 (p < 0.05)，但經由低、中及高劑量PPH餵食後，顯著降低其Caspase 3濃度含量 (p < 0.05)；Aβ誘導氧化壓力上升，在脂質過氧化部分，經餵食PPH後，三個劑量組別與未經處理的J20 AD模式鼠相比，皆顯著下降其MDA濃度 (p < 0.05)，且有提升SOD、CAT及GPx等抗氧化酵素活性的趨勢。綜合以上，本研究結果指出五個月大的J20 AD模式鼠早在相關病理特徵明顯產生前，即有認知行為能力上的障礙出現，而PPH的介入具有延緩相關病理特徵發展、改善氧化壓力作用程度及粒線體損傷而至細胞凋亡的情形發生，並具有改善J20 AD模式鼠學習記憶能力和降低焦慮的潛力。

In this study, J20 transgenic mice were used as Alzheimer’s disease (AD) animal model and fed with 200, 600 and 1000 mg/kg mouse/day designated as low, medium, and high dosage of pea protein hydrolysates (PPH) for 8 weeks, respectively. The effects of PPH on body weight, relative organ weight, serum biochemical values, cognitive behavior ability and AD-related pathogenesis in J20 AD mice were investigated. There were no significant differences in body weight and relative organ weight among groups of mice (p > 0.05). In serum biochemical values, each group of mice was no abnormal conditions. Hence, J20 AD mice fed with PPH for 8 weeks didn’t cause any adverse influence on health. Furthermore, based on morris water maze test, J20 AD mice had a tendency to improve learning and memory ability after being fed with medium dosage of PPH. According to open field test, all dosages of PPH significantly resulted in decreased total movement distance (p < 0.05) and increased the tendency of time spent on center (%) for J20 AD mice. The result indicated that PPH had the potential to reduce anxiety in J20 AD mice. Although concentrations of Aβ40 and Aβ42 in hippocampus were not significantly different between AD mice group and WT group, high dosage of PPH group significantly decreased concentration of Aβ40 (p < 0.05) and the medium and high dosage of PPH groups also significantly decreased concentration of Aβ42 (p < 0.05). In contrast with the slices of hippocampus, the positive expression of Aβ plaques in low, medium and high dosage of PPH groups had a downward trend; In concentration of β-secretase, J20 AD mice untreated group had a tendency to be higher than WT group, but there was not significant difference between them (p > 0.05). J20 AD mice were significantly decreased concentration of β-secretase as fed with medium and high dosage of PPH. In addition, concentration of Caspase 3 in J20 AD mice untreated group was significantly higher than WT group (p <0.05), but all dosages of PPH groups were significantly decreased the concentration of Caspase 3 (p <0.05). Aβ induced increase of oxidative stress in J20 AD mice, however, all dosages of PPH groups significantly decreased the concentration of malondialdehyde during lipid oxidation (p < 0.05). Besides, there were tendency to increase several antioxidative enzyme activity such as SOD, CAT and GPx after J20 AD mice fed with PPH. In conclusion, the above results indicated that five-month-old J20 AD mice had cognitive behavior impairments before development of relevant pathogenesis. The PPH showed potential to delay development of related pathogenesis, to ameliorate degree of oxidative stress and occurrence of apoptosis resulted from mitochondrial damage, to improve learning and memory ability as well as to reduce anxiety in J20 AD mice.

目錄
摘要 I
Abstract III
目錄 V
表目錄 IX
圖目錄 X
壹、前言 XII
貳、文獻回顧 3
一、阿茲海默症介紹 3
(ㄧ) 阿茲海默症起源與危機 3
(二) AD病徵 4
二、阿茲海默症相關病理因子 4
(一) 澱粉樣前體蛋白 (Amyloid precursor protein, APP) 4
(二) β端澱粉樣前體蛋白切割酵素 (beta-site APP cleaving enzyme 1,BACE1) 6
(四) Aβ介導氧化壓力與粒線體功能障礙 8
(五) 海馬迴 (Hippocampus) 10
三、抗氧化酵素系統 10
四、豌豆蛋白水解物之應用 12
(一) 豌豆蛋白 (Pea protein) 12
(二) 豌豆蛋白水解物 (Pea protein hydrolysates, PPH) 12
五、J20 AD模式鼠相關研究 13
六、研究目的與動機 13
參、材料與方法 15
一、實驗儀器與藥品試劑 15
(一) 儀器設備 15
(二) 藥品、試劑 16
(三) 酵素免疫分析套組 16
(四) 抗氧化酵素分析套組 17
(五) 動物試驗材料 17
二、實驗方法 17
(一) 試驗設計 17
(二) 豌豆蛋白水解物樣品製備 20
(三) 動物模式建立 20
(四) 動物行為能力試驗 23
(五) 實驗動物檢體處理 27
(六) 檢體蛋白質定量 (BCA assay) 29
(七) Enzyme-linked immunosorbent assay (ELISA) 29
(八) 抗氧化酵素 30
(九) 脂質過氧化測定 34
(十) 免疫螢光染色 (Immunofluorescence Staining) 35
三、統計分析 36
肆、結果與討論 37
一、管餵PPH對WT及J20 AD模式鼠體重及相對臟器重量之影響 37
二、管餵PPH對WT及AD模式鼠血清生化指數之影響 37
(一) 肝功能指數 38
(二) 腎功能指數 38
(三) 膽固醇含量 41
三、管餵PPH對WT及J20 AD模式鼠學習及記憶能力之影響 41
(ㄧ) 水迷宮試驗 41
(二) 曠野試驗 48
四、管餵PPH對WT及J20 AD模式鼠海馬迴中Aβ含量之影響 51
五、管餵PPH對WT及J20 AD模式鼠海馬迴中BACE1濃度之影響 58
六、管餵PPH對WT及J20 AD模式鼠海馬迴中Caspase3濃度之影響 60
七、管餵PPH對WT及J20 AD模式鼠海馬迴中MDA濃度之影響 60
八、管餵PPH對WT及J20 AD模式鼠海馬迴中抗氧化酵素之影響 63
伍、結論 68
陸、參考文獻 69

表目錄
表一、豌豆蛋白水解物劑量對WT及J20 AD模式鼠體重及相對臟器重量影響 39
表二、豌豆蛋白水解物劑量對WT及J20 AD模式鼠之血清生化指數影響 40

圖目錄
圖一、澱粉樣前體蛋白加工路徑 6
圖二、Aβ自組裝聚集示意圖 8
圖三、阿茲海默症中的氧化壓力與粒線體失序 9
圖四、粒線體中的抗氧化機制 11
圖五、試驗架構圖 19
圖六、水迷宮配置圖 25
圖七、曠野試驗配置 26
圖八、SOD抗氧化酵素反應系統 31
圖九、GPX抗氧化酵素反應系統 32
圖十、MDA反應式 35
圖十一、豌豆蛋白水解物對J20 AD模式鼠於平台逃逸試驗中逃逸時間之影響 43
圖十二、豌豆蛋白水解物劑量對J20 AD模式鼠於空間探索試驗中跨越原先平台位置次數之影響 44
圖十三、豌豆蛋白水解物劑量對J20 AD模式鼠於空間探索試驗中原先平台所在象限探索時間之影響 45
圖十四、豌豆蛋白水解物劑量對J20 AD模式鼠於空間探索試驗中游泳軌跡之影響 47
圖十五、豌豆蛋白水解物劑量對J20 AD模式鼠於曠野試驗中的移動總距離之影響 49
圖十六、豌豆蛋白水解物劑量對J20 AD模式鼠於曠野試驗中的中央區塊停留時間百分比之影響 50
圖十七、豌豆蛋白水解物劑量對J20 AD模式鼠於海馬迴中Aβ40含量之影響 52
圖十八、豌豆蛋白水解物劑量對 J20 AD模式鼠於海馬迴中Aβ42含量之影響 53
圖十九、豌豆蛋白水解物劑量對J20 AD模式鼠於海馬迴中澱粉樣斑塊沉積之影響 56
圖二十、豌豆蛋白水解物劑量對J20 AD模式鼠於海馬迴中β-secretase濃度之影響 59
圖二十一、豌豆蛋白水解物劑量對J20 AD模式鼠於海馬迴中caspase3濃度之影響 61
圖二十二、豌豆蛋白水解物劑量對J20 AD模式鼠於海馬迴中MDA濃度之影響 62
圖二十三、豌豆蛋白水解物劑量對J20 AD模式鼠於海馬迴中SOD活性之影響 64
圖二十四、豌豆蛋白水解物劑量對J20 AD模式鼠於海馬迴中CAT活性之影響 65
圖二十五、豌豆蛋白水解物劑量對J20 AD模式鼠於海馬迴中GPx活性之影響 67

附錄目錄
附錄 一、豌豆蛋白產品規格 78

許芸綺。(2021) 從豌豆蛋白水解物中分離及鑑定神經保護肽以對抗β-類澱粉誘導損傷的SH-SY5Y細胞，東海大學碩士論文，台中市。
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