臺灣博碩士論文加值系統

摘要
樟芝 (Antrodia camphorata) 為台灣特有的藥用真菌，其子實體常應用於各
種疾病的治療，如食品及藥物中毒所引起的腹瀉腹痛，高血壓，皮膚癢和抗癌。
類澱粉樣蛋白 (amyloid β-peptide ，Aβ) 被證實與阿茲海默症 (Alzhemer’s
disease，AD) 形成病因有密切關係，Aβ 會於腦部中沉積造成氧化壓力與發炎反
應使神經元受損，最終造成記憶學習能力的障礙。因此抗氧化能力與預防 AD 具
有極高的相關性，許多動物試驗結果皆顯示樟芝於體內亦提供有良好的抗氧化效
果，故篩選高效能的抗氧化能力萃取物將有助於獲得具預防 AD 之功效成分。
本研究以樟芝子實體、菌絲體萃取物做為試驗物質。分別以體外
α,α–diphenyl–β–picrylhydrazyl（DPPH）自由基清除試驗評估抗氧化能力以及成
分分析，再進行體外PC-12 神經纖維母細胞存活率、抗氧化與抗發炎能力試驗，
並於動物試驗以二十八天連續腦部輸注 Aβ40 建立 AD 模式大鼠以探討樟芝
發酵產物對 AD 大鼠記憶學習能力之影響，以及分析樟芝發酵產物對 AD 大鼠
大腦皮質與海馬迴組織中的抗氧化、抗發炎能力，和各表現蛋白沉積量與表現
量。本研究結果發現樟芝子實體比菌絲體多具有較高量的總黃酮與總酚含量。在
DPPH 自由基清除能力方面，以 300 μg/mL 時樟芝子實體水萃取物之清除能力
為最強 (p<0.05)。在體外細胞試驗之結果顯示，濃度為 1.25 ppm 時，抑制 Aβ40
的細胞毒性能力依強至弱順序為樟芝菌絲體水萃取物、lovastatin (正控制組)、子
實體水萃取物、子實體乙醇萃取物、菌絲體乙醇萃取物 (p<0.05)。而當樣品濃度
為 1.25 ppm 時，抑制 Aβ25-35 的細胞毒性能力依強至弱順序為子實體水萃取
物、菌絲體水萃取物、子實體乙醇萃取物、菌絲體乙醇萃取物、lovastatin
(p<0.05)。在對抗Aβ 誘發氧化與發炎反應之細胞試驗中，以 Aβ40 (187.5 nM)、
Aβ25-35 (10 μM) 處理 PC12 細胞後會造成 malondialdehyde (MDA) 與
reactive oxygen species (ROS) 濃度均顯著增加 (p<0.05)，但此 MDA 與 ROS 濃
度的上升可因加入子實體與菌絲體水與乙醇萃取物 (1 ppm) 而有效的再度被降
低，而又以子實體水萃取物效果更佳 (p<0.05)。 PC-12 細胞之 Tau 蛋白表現量
會因Aβ40 之處理而大量表現。添加樟芝子實體水萃取物則有較為顯著降低 Tau 蛋白表現量的效果。在動物記憶學習試驗之結果顯示，餵食子實體與菌絲體的
AD 大鼠可縮短參考記憶試驗與工作記憶試驗的搜尋時間 (p<0.05)，此外，子實
體組更可在空間性探測試驗中延長於目標象限的搜尋時間 (p<0.05)。在腦部輸注
Aβ 的大腦皮質與海馬迴組織中發現 MDA 與 ROS 濃度均顯著增加
(p<0.05)，但此 MDA 與 ROS 濃度的上升可因餵食子實體與菌絲體而有效的再
度被降低 (p<0.05)。由大鼠大腦皮質與海馬迴組織之 Aβ40、BACE、Tau 蛋白
表現量可發現，與 Normal 組比較，Aβ 組的大腦皮質組織中有大量 Aβ40、
BACE、Tau 蛋白的表現量。餵食樟芝子實體組則有較為顯著降低 Aβ40、Tau 蛋
白表現量的效果。由大腦皮質與海馬迴組織中 Aβ40、sAPPα 蛋白質沉積表現量
可發現，與 Normal 組比較，Aβ 組的大腦皮質組織中有大量 Aβ40 的沉積。餵
食樟芝子實體組則有較為顯著降低 Aβ40 累積量的效果。Normal 組的大腦皮質
組織中有大量 sAPPα 的沉積。Lovastatin 組及樟芝子實體組與Aβ 組比較則有
較為顯著提升 sAPPα 累積量的效果。

Abstract
Antrodia camphorate is a Taiwan-specific medical fungus, and its fruit-body is
often applied to the treatment of various diseases such as sitotoxism and drug toxicity
induced diarrhea and abdominalgia, hypertension, pruritus and cancer. Amyloid
β-peptide (Aβ) is proven to closely associate with pathogens of Alzheimer’s diseases
(AD). The deposition of Aβ in brain causes oxidative stresses and inflammatory
responses, and leads to neuron damages as well as the impairments of learning and
memory. Therefore, antioxidant capabilities are highly associated with AD
preventions. A number of animal experiments have indicated that A. camphorata
would provide excellent in vivo antioxidant effect, so antioxidant effect is probable to
be used as the important marker for AD prevention. This study concerned in the
research and development of an A. camphorata fermentation product with the
functions of prophylaxis and amelioration of AD. AD prevention factors of
A.camphorata fruit-body and mycelium including DPPH scavenging effect, anti-Aβ
neurocytotoxicity, antioxidative and anti-inflammatory capacities were measured in
this study. AD rat model established through continuous injection of Aβ40 for 28
consecutive days was used to evaluate the effect of A. camphorata fermentation
products on learning and memory abilities, as well as oxidative and inflammatory risk
factors in cerebral cortex and hippocampus tissues. The results showed that the water
extract of fruit-body had the most potent DPPH scavenging ability among all groups.
The ability for the protection against Aβ40 cytotoxicity were the water extract of
mycelium, lovastatin, the water extract of fruit-body, the ethanol extract of fruit body
and the ethanol extract of mycelium in sequence expressed as using the concentration
at 1.25 ppm. The ability for the protection against Aβ25-35 cytotoxicity were the
water extract of fruit-body, the water extract of mycelium, the ethanol extract of
fruit-body, the ethanol extract mycelium, and lovastatin in sequence expressed as
using the concentration at 1.25 ppm. In the cell test regarding the prevention against
Aβ-induced oxidative stress and inflammatory response, malondialdehyde (MDA) and reactive oxygen species (ROS) expression were both significantly increased by
the treatment of Aβ40 (187.5 nM) and Aβ25-35 (10 μM) in PC 12 cell (p<0.05).
However, these damages were be reversed by the treatment of water and ethanol
extract of fruit body and mycelium, in which the water extract of fruit body performed
the best effect. The Tau protein in PC 12 cells was expressed by the treatment of Aβ40,
as compared with Normal group. However, this expression was supressed by the
water extract of fruit body. Furthermore, the results of the experiments concerning
animal learning and memory ability showed that AD rats fed fruit-body and mycelium
have shorter searching time in the reference memory experiments and working
memory experiments (p<0.05). In addition, the fruit-body group would extend the
searching time around target quadrants in the spatial exploration tests (p<0.05). The
concentration of MDA and ROS in cerebral cortex and hippocampus tissues of Aβ
group were higher by 2, 7.1 and 2 times than that of the Normal group (p<0.05), but
the increased MDA and ROS levels may be effectively brought down by feeding
fruit-body and mycelium (p<0.05). According to the result of the Aβ40 and sAPPα
protein deposition in cerebral cortex and hippocampus tissues, a large amount of
Aβ40 deposit is discovered in Aβ group, as compared with the Normal group. An
obvious decreasing of Aβ40 deposition was shown in fruit-body group. According to
the expression of Aβ40, BACE, and Tau protein in hippocapus and cortex tissue,
Aβ40, BACE, and Tau were significantly expressed in Aβ-infused rat. However, the
fruit body treatment was able to perform more effect on reversing the damage than
mycelium treatment . Lower sAPPα deposition was also generated in cortex tissues in
the Aβ group than in Normal group, but a remarkable increase of sAPPα accumulation
is further observed in the lovastatin group and fruit-body group as compared with the
Aβ group. In the future work, the result of this study was expected to be the base on
the study of the functional ingredients and mechanism of AD prevention of A.
camphorate.

目 錄
謝辭………………………………………………………………...…………..Ⅰ
縮寫表…………………………………………………………...……………..Ⅱ
中文摘要…………………………………………………………...…………..Ⅳ
英文摘要…………………………………………………………...…………..Ⅵ
目錄………………………………………………………………...…...............Ⅷ
前言……………………………………………………………….......................1
壹、文獻回顧…………………………………………………………………...4
貳、實驗動機及實驗架構…………………………………………………….. 25
參、實驗材料與方法…………………………………………………………...28
一、實驗材料…………………………………………………………………...28
二、實驗方法…………………………………………………………………...31
肆、結果…………………………………………………………………….......48
一、成分分析………..…...……………………………………………………..48
二、抗氧化活性之分析………………………………………………………...48
三、樟芝子實體與菌絲體萃取物抑制 Aβ40、 Aβ25-35 對 PC-12 細胞毒殺之研
究………………………………………………………………………………...51
四、樟芝子實體與菌絲體對 Aβ40 腦部輸注之阿茲海默症大鼠記憶學習能力之
影響……………………………………………………………………………...68
伍、討論……………………………………………………………...................83
陸、結論………………………………………………………….……………..92
柒、參考文獻…………………………………………………………………...98
附錄、已發表之文章………………………………………………………......119
表次索引
表一、樟芝菌絲體粉末成分分析表……………………………………………32
表二、樟芝發酵產物改善 Aβ40 腦部輸注之阿茲海默症大鼠記憶學習能力試驗
之動物分組………………………………………………………………………38
表三、樟芝子實體與菌絲體之水與乙醇萃取液之總黃酮與總酚、總多醣含量
……………………………………………………………………………………49
表四、樟芝子實體與菌絲體之水與乙醇萃取物清除 DPPH 自由基能力…..50
表五、樟芝子實體與菌絲體對於阿茲海默症預防效果之比較……………………..93
圖次索引
圖一、樟芝子實體形態….....................................................................................5
圖二、樟芝菌絲形態….........................................................................................7
圖三、類澱粉樣前驅蛋白質之酶切…...............................................................15
圖四、研究計畫大綱…………………………………………………...............26
圖五、ALZET 腦部輸注幫浦………………………………………………....40
圖六、樟芝發酵產物改善阿茲海默症大鼠之記憶學習試驗日程表………...41
圖七、腦部輸注 Aβ40 之手術流程…………………….…………………….42
圖八、水迷宮裝置與分區域示意圖………………………………….………..44
圖九、不同濃度之 Aβ40、Aβ25-35 對於 PC-12 細胞存活率之影響……..52
圖十、不同濃度之乙醇對於 PC-12 細胞存活率之影響…………………….53
圖十一、不同濃度之樟芝子實體與菌絲體水與乙醇萃取物與 Lovastatin 對 Aβ40
毒殺 PC-12 細胞之影響………………………………………………...……..55
圖十二、相同濃度之試驗物質對 Aβ40 毒殺 PC-12 細胞存活率之影
響……………………………………………………………………...................56
圖十三、相同濃度之試驗物質對 Aβ40 毒殺 PC-12 細胞存活率之影
響………...............................................................................................................57
圖十四、不同濃度之樟芝子實體與菌絲體水與乙醇萃取物與 lovastatin 對
Aβ25-35 毒殺 PC-12 細胞之影響………………………………....................58
圖十五、相同濃度之試驗物質對 Aβ25-35 毒殺 PC-12 細胞存活率之影
響………………………………………………………………………………...59
圖十六、相同濃度之試驗物質對 Aβ25-35 毒殺 PC-12 細胞存活率之影
響………………………………………………………………………………...60
圖十七、不同濃度之其他市售樟芝菌絲體產品水與乙醇萃取物對 Aβ40 毒殺 PC-12 細胞之影響……………………………………………………………..61
圖十八、不同濃度之其他市售樟芝菌絲體產品水與乙醇萃取物對 Aβ25-35 毒殺
PC-12 細胞之影響……………………………………………………………..63
圖十九、相同濃度之試驗物質對 Aβ40 毒殺 PC-12 細胞中 MDA 含量之影
響……………………………………………………….......................................64
圖二十、相同濃度之試驗物質對 Aβ25-35 毒殺 PC-12 細胞中 MDA 含量之影
響…………………………………………….…………......................................65
圖二十一、相同濃度之試驗物質對 Aβ40 毒殺 PC-12 細胞中 ROS 含量之影
響………...............................................................................................................66
圖二十二、相同濃度之試驗物質對 Aβ25-35 毒殺 PC-12 細胞中 ROS 含量之影
響...........................................................................................................................67
圖二十三、相同濃度之試驗物質對 Aβ40 毒殺 PC-12 細胞中 Tau protein 蛋白
表現量之影響.......................................................................................................69
圖二十四、樟芝子實體與菌絲體對 Aβ40 腦部輸注之大鼠於參考記憶試驗中之
逃逸時間................................................................................................................70
圖二十五、樟芝子實體與菌絲體對 Aβ40 腦部輸注之大鼠在 Probe 試驗於目標
象限之游泳路徑....................................................................................................71
圖二十六、樟芝子實體與菌絲體對 Aβ40 腦部輸注之大鼠在 Probe 試驗於目標
象限之游泳時間....................................................................................................72
圖二十七、樟芝子實體與菌絲體對 Aβ40 腦部輸注之大鼠於工作記憶試驗中之
記憶學習能力........................................................................................................73
圖二十八、樟芝子實體與菌絲體對於腦部輸注 Aβ40 大鼠之大腦皮質與海馬迴
組織中 MDA 含量之影響...................................................................................75
圖二十九、樟芝子實體與菌絲體對於腦部輸注 Aβ40 大鼠之大腦皮質與海馬迴
組織中 ROS 含量之影響....................................................................................76
圖三十、樟芝子實體與菌絲體對於腦部輸注 Aβ40 大鼠之大腦皮質組織中
Aβ40、BACE、Tau protein 蛋白質表現量之影響............................................78
圖三十一、樟芝子實體與菌絲體對於腦部輸注 Aβ40 大鼠之大腦海馬迴組織中
BACE、Tau protein 蛋白質表現量之影響.........................................................79
圖三十二、樟芝子實體與菌絲體對於腦部輸注 Aβ40 大鼠之大腦皮質與海馬迴
組織中 Aβ40 蛋白質沉積量之影響...................................................................80
圖三十三、樟芝子實體與菌絲體對於腦部輸注 Aβ40 大鼠之大腦皮質與海馬迴
組織中 sAPPα 蛋白質沉積量之影響.................................................................82

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