在腦部的退化性疾病當中，以阿滋海默症(Alzheimer’s disease, 以下簡稱AD)最受矚目。其主要成因為大量β型類澱粉蛋白斑塊(β-amyloid plaques, 以下簡稱Aβ plaques)累積所造成的腦部病變。近來的研究顯示，長期過量攝取含鋁離子的水或食物，容易引起Aβ plaques累積於腦部邊緣系統，導致AD的發生。AD是一種漸進性腦細胞退化疾病，患者的腦部記憶功能會逐漸衰退，導致失能，進而造成癡呆。近年來AD病患體內微循環障礙的病理徵象，漸為臨床醫師所重視。過去研究顯示，靈芝子實體萃取物可以有效促進免疫功能、改善循環與增強抗氧化作用。本研究目的在探討松杉靈芝子實體萃取物，對三氯化鋁誘導腦部病變改善作用。評估對於提昇血液動力學、學習記憶能力、減少β型類澱粉蛋白斑塊及抗氧化能力之影響。
本研究設計在同時使用多種不同的檢測方法包括 : 水迷宮測量(Morris Water Maze)、磁振造影測試(MRI Test)、腦部血流量測量(ASL-rCBF Test)、磁振頻譜的腦部代謝物質測量(MRS Test)、血液血球分析、血液流變參數分析以及血清生化學參數分析、大鼠腦脊髓液定量白蛋白與Aβ濃度、血液及腦組織抗氧化能力分析、IHC免疫組織化學染色分析Aβ plaques狀態等指標，進行三氯化鋁誘發阿茲海默症大鼠各項病態檢測與餵食松杉靈芝子實體萃取物前後各項指標的變化。
研究結果顯示經三氯化鋁誘發阿茲海默症的腦病變組大鼠，在全血黏度、血漿黏度、纖維蛋白原濃度、血清HsCRP濃度、腦脊髓液中Aβ / Il6 / TNF-α濃度、紅血球中乙醯膽鹼酯&;#37238;(Acetylcholinesterase, AChE-RBC)與MDA活性、腦部皮質與海馬迴組織中MDA活性、腦部皮質與海馬迴組織中Aβ plaque數量皆顯著高於正常組大鼠；三氯化鋁誘導腦病變組中大鼠中紅血球變形度、腦部血流量及N-acetyl aspartate (NAA)濃度則顯著低於正常組大鼠。經松杉靈芝子實體熱水萃取物YL1或松杉靈芝子實體乙醇萃取物YL2 60天後，皆能明顯改善三氯化鋁誘發阿茲海默症病態大鼠的血液黏度、氧化壓、NAA濃度、乙醯膽鹼酯&;#37238;濃度、Aβ plaque累積量與腦部血流量，並於水迷宮試驗中顯示學習與記憶能力的改善。
本研究結合血液流變學與MRI動脈自旋標記(Arterial Spin Labeling, ASL)技術，呈現腦部功能障礙大鼠體內的血流動力學變化，證實松杉靈芝子實體萃取物具有改善三氯化鋁誘導大鼠大腦病變、保護腦部神經血管的作用，為預防或治療阿茲海默症提供新的契機。

Alzheimer’s disease (AD) has received the most attention among all neurodegenerative disorders because it is considered one of the costliest diseases to society in developed countries. The causes and progression of the disease are not well understood; some studies maintain that it is caused by the pathological changes to the brain due to accumulation of beta-amyloid plaques (Aβ plaques). Recent research has indicated that prolonged, excessive consumption of food or water containing aluminum results in the accumulation of Aβ plaques in the limbic system of the brain, leading to AD. As a progressive degenerative disease of the brain cells, AD causes patients’ memory and other brain functions to deteriorate gradually, leading to functional loss and eventually dementia. In recent years, clinical physicians have come to realize the importance of the pathological signs of microcirculation disturbances in patients with AD. Previous research has indicated that the extract of Ganoderma lucidum (G. tsugae) can effectively stimulate autoimmune functions, improve metabolism, and enhance anti-oxidation. The objective of this study is to explore how the herb affects hemodynamics, learning and memory functions, the reduction of Aβ plaques, and oxidation inhibition by administering extracts of G. tsugae fruiting bodies to rats exposed to aluminum tri-chloride (AlCl3).
The study uses an experimental design utilizing multiple measurement and quantitation methods including the Morris water maze test, Magnetic Resonance Imaging test (MRI), Arterial Spin Label–regional Cerebral Blood Flow test (ASL-rCBF test), Magnetic Resonance Spectroscopy (MRS) test, blood cell count analysis, hemorheological parameter analysis, serum chemistry parameter analysis, cerebrospinal fluid test and Aβ plaque concentration, as well as anti-oxidation capacity test on blood plasma viscosity and fibrinogen concentration, serum HsCRP concentration, Aβ / Il6 /TNF-α concentration and tests on acetyl cholinesterase (AChE-RBC) activity and malondialdehyde concentration. Through combinative implementation of these methods study hopes to examine the changes in the indicators of various AD symptoms before and after rats, afflicted with AD due to AlCl3, were given G. tsugae fruiting bodies.
In addition, the study also carries out comparative research to explore more specific phenomena using multiple modalities.
Results of this study indicate that AD rats, in the positive control group, induced by AlCl3 showed higher levels of whole blood viscosity, blood plasma viscosity, fibrinogen concentration, serum HsCRP concentration, Aβ / Il6 /TNF-α concentration in the cerebrospinal fluid, acetylcholinesterase (AChE-RBC) activity and malondialdehyde (MDA) in red blood cells, and MDA and Aβ plaque in the cerebral cortex and hippocampal tissue than those in the control group. Conversely, the rats in the positive control group exhibited significantly lower erythrocyte deformability, cerebral blood flow, and N-acetylaspartate (NAA) concentrations than those in the control group. The rats in the YL1 (G. tsugae extracts by using hot water) and YL2 (G. tsugae extracts by using ethanol) groups, which were exposed to AlCl3 and then orally given the G. tsugae extract for 60 days, exhibited marked improvement in blood viscosity, oxidative stress, NAA concentrations, AChE-RBC concentrations, Aβ plaque accumulation levels, and cerebral blood flow. The results of the water maze tests also indicated improvement in learning and memory. Hemorheology and MRI arterial spin labeling technology were combined in this study to demonstrate changes in the hemodynamics of rats with AlCl3-induced brain dysfunction. It is, therefore, the conclusion of this study that treatment with G. tsugae can protect neural nerves and blood vessels as well as combat related pathological changes induced by AlCl3 in rats. The study hopes to provide a reference point for future researches on the preventive or reversal methods for Alzheimer’s disease.

誌謝 i
CONTENT ii
圖目錄 viii
表目錄 xi
附圖 xiii
中文摘要 xiv
ABSTRACT xvi
第一章 緒論 1
1.1 阿茲海默症與大腦類澱粉血管病變 2
1.2 靈芝簡介 9
1.2.1 靈芝主要成分及功效 13
1.2.2 從自由基的清除能力評估靈芝的抗氧化作用 17
1.3 文獻回顧與研究特點 19
1.4 血液流變學參數 23
1.4.1 黏度 23
1.4.2 血漿黏度 26
1.4.3 血液黏度 26
1.4.4 物體黏彈性及黏彈流體之介紹 29
1.4.5 血液的黏彈流體特性及其影響因素 29
1.4.6 紅血球變形與量測原理 31
1.4.7 紅血球聚集性與量測原理 32
1.5 類澱粉蛋白的來源、作用與清除機制 32
1.5.1 類澱粉蛋白的來源 32
1.5.2 類澱粉蛋白與細胞膜的作用 37
1.5.3 類澱粉蛋白的清除機制 39
1.6 實驗假說、設計與研究目的 41
第二章 材料與方法 44
2.1 實驗動物 44
2.2 實驗設計與設備材料 45
2.2.1 實驗設備 45
2.2.2 血液黏度檢測儀驗 45
2.2.3 自動血球計數分析儀 46
2.2.4 自動血清生化分析儀 47
2.2.5 自動血清免疫分析儀 47
2.2.6 紅血球變形及聚集測試儀 48
2.2.7 水迷宮試驗設備 49
2.2.8 核磁共振影像造影設備 50
2.2.9 實驗試藥 52
2.3 實驗步驟與方法 53
2.3.1 實驗動物分組 53
2.3.2 大腦病變大鼠的誘發 53
2.3.3 試驗物質及藥物的投予 53
2.3.4 大鼠水迷宮試驗 54
2.3.5 MRI腦部血液流量測定和磁振血管造影成像分析 55
2.3.6 大鼠犧牲前經由枕骨大孔以25號針頭抽取腦脊髓液 57
2.3.7 血液生化分析 58
2.3.8 血液常規學與血液流變學檢測(Hematology/Hemorheology) 60
2.3.9 IHC染色以及分析海馬迴和皮層中Ab42和iNOS 60
2.3.10 檢測大鼠腦脊髓液中Il6及TNF-α 61
2.3.11 檢測大鼠腦組織SOD，Catalase，GSH-Px及MDA 61
2.3.12 以剛果紅(Congo red)染色法觀察大鼠腦部血管內&;szlig;–amyloid 62
2.3.13 定量大鼠CSF中的&;szlig;–amyloid 62
2.4 統計分析 62
第三章 結果 63
3.1 體重、攝水量及攝食量 63
3.2 生化學分析(Results of Biochemistry) 65
3.3 YL1和YL2顯著改變經三氯化鋁誘導大鼠的血液流變機轉 67
3.3.1 血液常規學檢測結果(Results of Hematology) 67
3.3.2 血液流變學檢測結果(Results of Hemorheology) 69
3.4 YL1和YL2能顯著改善經過三氯化鋁誘導大鼠的抗氧化能力 73
3.4.1 大鼠腦部超氧歧化&;#37238;(Superoxide dismutase，SOD)分析結果 73
3.4.2 大鼠腦部觸&;#37238;(Catalase)分析結果 73
3.4.3 大鼠腦部穀胱甘&;#32957;過氧化物&;#37238;(Glutathione peroxidase)分析結果 74
3.4.4 大鼠腦部丙二醛(Malondialdehyde，MDA)分析結果 74
3.5 YL1和YL2顯著改善經過三氯化鋁誘導大鼠的局部腦血流量 76
3.5.1 核磁共振(MRI)檢測結果 76
3.5.2 YL1和YL2能顯著改善經過三氯化鋁誘導大鼠的NAA濃度 78
3.5.3 YL1和YL2能顯著改善經過三氯化鋁誘導大鼠腦部血管損傷 79
3.6 免疫組織染色法檢測結果 81
3.6.1 YL1和YL2顯著降低三氯化鋁誘導大鼠腦部一氧化氮合成&;#37238;的表現 81
3.6.2 YL1和YL2松山靈芝子實體萃取物顯著降低沉積在海馬迴和大腦皮質的Aβ plaques 82
3.7 大鼠大腦組織使用剛果紅(Congo red)與血液抹片劉氏(Liu)染色法檢測結果 84
3.8 YL1和YL2顯著改善經過三氯化鋁處理後的大鼠之記憶能力 87
3.8.1 參考記憶試驗(Reference Memory Task) 87
3.8.2 空間性探測試驗(Probe Trial) 88
第四章 討論 90
4.1 三氯化鋁誘導大鼠的腦部病理變化分析 90
4.2 大鼠頸靜脈與下腔靜脈血液流變性質的差異分析 92
4.3 YL1與YL2對三氯化鋁誘導大鼠的抗發炎與抗氧化作用 93
4.4 YL1與YL2改變三氯化鋁誘導大鼠血液流變的機制 95
4.5 纖維蛋白原(Fibrinogen)與β型類澱粉蛋白的作用 98
4.6 YL1與YL2增加三氯化鋁誘導大鼠腦部血流量的作用機制 100
4.7 YL1與YL2降低三氯化鋁誘導大鼠AChE-RBC活性與增加腦部NAA活性的臨床意義 103
4.8 YL1與YL2增進三氯化鋁誘導大鼠認知記憶能力的可能機制 105
4.9 結語 108
第五章 未來展望 110
第六章 參考文獻 112
第七章 附圖 121

圖目錄

圖A (左)德國精神科病理醫師阿滋海默(German psychiatrist Alois Alzheimer) 與(右)他的病人歐葛斯特(Auguste Deter ) 4
圖B 正常情況下，腦部神經元與血管是耦合的(Neurovascular coupling) 22
圖C Mutations in the APP gene and their relationship to the amino acid sequence of the Aβ peptide 35
圖D β-amyloid (Aβ) plaque的由來 35
圖E 類澱粉前驅蛋白質(Amyloid precursor protein, App)是類澱粉斑塊的前驅蛋白質。在阿茲海默症中，這些成塊型式的蛋白質會影響腦部海馬迴和腦部皮質區，進而中斷腦部神經元的運作 36
圖F 全自動旋轉式血液黏度檢測儀(Auto-Rotational Viscometer, HRD) 45
圖G 軌道式全自動血球計數分析儀(LH750, Beckmen) 46
圖H 模組軌道式全自動血清生化分析儀(P800, Roche) 47
圖I 模組軌道式全自動血清免疫分析儀(E170, Roche) 47
圖J 半自動紅血球變形及聚集測試儀(LG-B-190型Ektacytometer) 48
圖K 水迷宮試驗設備:水池、攝影機及電腦(購自國揚生技股份有限公司). 49
圖L BRUKER 7T BioSpec 70/30核磁共振造影(MRI)儀器 51
圖2.1 SPF級的雄性Wistar大鼠 44
圖2.2 實驗試藥之準備，圖左:三氯化鋁(AlCl3)，圖中:靈芝極性萃取物(YL1)圖右:靈芝非極性萃取物(YL2) 。 52
圖2.3 採集腦脊髓液的步驟(1~7)。大白鼠犧牲前經由枕骨大孔以25 號針頭抽取腦脊髓液，以供測量CSF-AI與分析腦脊髓液細胞之促發炎細胞素IL-1β，IL-6 和TNF-α濃度變化 58
圖2.4 採集各組大鼠腹腔靜脈(左)和頸靜脈(右)的血液 59
圖3.1 大鼠腦脊髓液中&;szlig;-amyloid濃度的檢測。結果顯示，經三氯化鋁誘導大鼠的腦脊髓液中&;szlig; -amyloid的濃度顯著高於正常組，經YL1或YL2治療後的大鼠腦脊髓液中&;szlig; -amyloid的濃度則顯著低於三氯化鋁誘導腦病變組 67
圖3.2 In vitro大鼠血液混合&;szlig;-amyloid的黏度檢測將正常大鼠的血液添加&;szlig;-amyloid（1-42）溶液後，於剪切率(Shear rate)30s-、70s-和120s-的流場條件下，皆顯著表現全血黏度增加。(WB : Viscosity of whole blood in normal rats) 72
圖3.3 大鼠大腦兩側半球的皮層、皮層下白質和蛛網膜下腔等處的核磁共振(MRI)梯度回波(FLASH)序列模式掃描。結果顯示無論正常組大鼠、三氯化鋁誘導腦病變組大鼠、YL1組大鼠或YL2組大鼠的腦皆未偵測到有微出血(Micro bleeds)或血鐵質(Hemosiderin)出現 76
圖3.4 大鼠腦部前區各部分海馬迴和皮質層的rCBF(局部腦血流量)分析。結果顯示，三氯化鋁誘導腦病變組的海馬迴（黑色箭頭處）和皮質層（白色箭頭處）的rCBF呈顯著下降，而經餵食YL1和YL2的大鼠其rCBF顯著上升 77
圖3.5 大鼠腦部NAA(N-acetyl aspartate)，Choline及 Creatine的分析。結果顯示，三氯化鋁誘導腦病變組的N/C ratio顯著低於正常組。而2個治療實驗組的N/C ratio則顯著高於三氯化鋁誘導腦病變組 79
圖3.6 TOF-MRA掃描的血管造影圖像結果。可見各組在大腦海馬迴區域（紅色圓圈處）的血管強度不同。正常組(A)的MRI圖像顯示腦血管訊號非常密集，而三氯化鋁誘導腦病變組(B)的腦血管訊號密度明顯較低。YL1和YL2兩組(C和D)的腦血管訊號密度高則明顯高於三氯化鋁誘導腦病變組(B)。 80
圖3.7 大鼠腦部皮質區iNOS的IHC染色分析。三氯化鋁誘導腦病變組大鼠腦部皮質區iNOS的表現顯著高於正常組。而YL1組與YL2組大鼠腦部皮質區iNOS的表現則顯著低於三氯化鋁誘導腦病變組 81
圖3.8 切片染色結果下，於腦皮質以及海馬迴部分經影像分割技術定量之Aβ類澱粉蛋白斑塊面積(每組樣本數為六隻)，由趨勢可發現YL1與YL2對於斑塊之對應關係略有不同，但都有達到降低斑塊總面積量效果 82
圖3.9 8~12週的雄性Wistar大鼠經三氯化鋁誘導5個月及經餵食YL1 和 YL2 2個月後以免疫組織化學染色法(IHC)分析大鼠腦部海馬迴(Hippocampus, HIP)及皮質(Neocortex, NCX)之β-類澱粉蛋白沉積之情形。結果顯示，積聚在三氯化鋁誘導腦病變組大鼠的海馬迴和皮質層的Ab斑塊數量顯著多於正常組，而積聚在YL1和YL2組大鼠之海馬迴和皮質層的Ab斑塊數量少於三氯化鋁誘導腦病變組 83
圖3.10 Advanced IHC stain result of the rats treat with AlCl3.. (A)The IHC stain shows Abs deposits in diffuse plaques. (B) The IHC stain shows Abs (red) accumulating around neurons 84
圖3.11 大鼠海馬迴血管剛果紅染色分析。三氯化鋁誘導腦病變組大鼠海馬迴血管內β-類澱粉蛋白沉積量顯著高於正常組。而YL1組與YL2組大鼠腦部海馬迴血管週圍β-類澱粉蛋白沉積量則顯著低於三氯化鋁誘導腦病變組 85
圖3.12 大鼠血液抹片劉氏染色法分析。三氯化鋁誘導腦病變組大鼠血液抹片中紅血球聚集的程度(RBC aggregation ++)顯著大於正常組(RBC aggregation - )。而YL1組與YL2組大鼠血液抹片中紅血球聚集的程度(RBC aggregation +)顯著低於三氯化鋁誘導腦病變組 86
圖3.13 各組在參考記憶試驗中的表現結果YL1和YL2對經過三氯化鋁處理後大鼠的逃生潛伏期(左)以及搜索距離(右)之影響]。三氯化鋁誘導大鼠呈現長時間的逃生潛伏期和搜索距離，接受松杉靈芝子實體萃取物治療後，大鼠的逃生潛伏期和搜索距離顯著低於三氯化鋁誘導腦病變組 87
圖3.14 YL1和YL2療法對三氯化鋁誘導大鼠停留在對側象限(II)和目標象限(IV)時間的影響。餵食松杉靈芝子實體萃取物後，大鼠停留在目標象限的搜索時間顯著增加，在對向象限停留和搜索時間則顯著增加 88
圖3.15 空間記憶試驗顯示，休息平台移除，餵食YL1和YL2 的大鼠仍能記住原先放休息平台位置，並會在原休息平台位置徘徊 89
附圖一 長時間的MRI掃描下（半年期間），可以觀察到治療組中，不管是使用YL1還是YL2進行治療，在停藥之後，其腦部血流量均會快速下降至AD誘發大鼠之水平(每組樣本數為二隻) 121
附圖二 在停止使用YL1、YL2靈芝萃取物治療的大鼠，其腦部代謝物質NAA的含量亦緩慢下降，下降的趨勢與腦部血流量下降趨勢非常相像，但是過程稍微緩慢一些 121
附圖三 本研究中所涵蓋之實驗項目以及研究測試結果關聯樹狀圖 122
表目錄
表 1 台灣地區常見的野生靈芝種類及特性(2010，許瑞祥). 11
表 2 正常組、三氯化鋁誘導腦病變組、YL1組及YL2組試驗物質及藥物投予之劑量與體積……………. ……………………………………………… 54
表 3.1 8~12週的雄性Wistar大鼠經三氯化鋁誘導5個月及經餵食YL1和YL2 2個月後體重之變化 63
表 3.2 8~12週的雄性Wistar大鼠經三氯化鋁誘導5個月及經餵食YL1和YL2 2個月後平均攝水量與平均攝食量之變化 64
表 3.3 經過五個月的氯化鋁處理後呈現阿茲海默症狀的大鼠，在接受兩個月的YL1或YL2處理後其血液/腦脊髓液/腦組織均質液的生化分析結果 66
表 3.4 8~12週的雄性Wistar大鼠經三氯化鋁誘導5個月及經餵食YL1和YL2 2個月後來自頸靜脈之血液參數值變化之比較 68
表 3.5 大鼠經三氯化鋁誘導5個月及經餵食YL1和YL2 2個月後腹腔靜脈之血液參數值變化表 68
表 3.6 8~12週的雄性Wistar大鼠經三氯化鋁誘導5個月及經餵食YL1和YL2 2個月後取自頸靜脈之血液流變學參數值變化之比較 70
表 3.7 8~12週的雄性Wistar大鼠經三氯化鋁誘導5個月及經餵食YL1和YL2 2個月後取自腹腔靜脈之血液流變學參數值變化之比較 71
表 3.8 靈芝子實體萃取物對三氯化鋁誘導大鼠腦部海馬迴及皮質層SOD, Catalas, Glutathione peroxidase活性的影響及 MDA在腦部海馬迴、皮質層及頸靜脈血中紅血球的活性變化結果 75
表 3.9 比較正常組、三氯化鋁誘導腦病變組、YL1和YL2在海馬迴和皮層的rCBF分布圖。rCBF量化分析包含四個不同區域

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