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研究生:蔡聯欣
研究生(外文):Tsai, Lien-Hsin
論文名稱:膽固醇不足加劇星狀神經膠細胞因麩胺酸所致之細胞死亡
論文名稱(外文):Cholesterol Deficiency Aggravates Glutamate-induced Cell Death in Astrocyte Cultures
指導教授:周韻家
指導教授(外文):Chou, Yun-Chia
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物藥學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:49
中文關鍵詞:星狀神經膠細胞海馬迴膽固醇興奮性毒性麩胺酸
外文關鍵詞:astrocytehippocampuscholesterolexcitotoxicityglutamate
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中文摘要
膽固醇為細胞膜的主要成分,其功能為維持細胞膜的物理特性,並參與膜上蛋白質的功能。目前的研究指出老化或阿滋海默症會造成腦部組織的膽固醇含量下降。另外,本實驗室先前的研究發現膽固醇不足會加劇海馬迴混和細胞培養的麩胺酸興奮性毒性,以證實膽固醇不足與腦細胞死亡的關係。而海馬迴混和細胞培養主要由星狀神經膠與神經細胞所組成,且兩者在腦部的生理功能與膽固醇的代謝能力不同,所以本論文利用海馬迴星狀神經膠細胞或神經細胞培養,來探討膽固醇不足對於不同細胞種類之麩胺酸興奮性毒性的影響。
我利用 lovastatin 與 b-cyclodextrin 的處理來抑制細胞內膽固醇的生合成及移除細胞膜上的膽固醇,以降低細胞的膽固醇含量。發現星狀神經膠細胞的增生能力在 lovastatin 處理期間沒有降低,且 lovastatin 與 b-cyclodextrin 的處理會降低星狀神經膠細胞的膽固醇含量而不改變細胞週期。此外,我以乳酸脫氫酶由細胞質溢出到細胞間的量或細胞還原 WST-1 試劑的能力,來測量細胞膜的損壞程度或細胞代謝活性,以推斷細胞死亡的數量。我發現海馬迴星狀神經膠細胞經麩胺酸處理 6 小時後,再將細胞置於先前的培養基中培養 8 小時 (回復期),會於回復期引起延遲性的細胞膜損壞,而膽固醇不足加劇麩胺酸對星狀神經膠細胞之細胞膜的損壞。若延長麩胺酸處理到 12 小時並給予 8 小時的回復期後,則會引起細胞膜的損壞與代謝活性的下降,導致細胞死亡,而膽固醇不足則會加劇麩胺酸對星狀神經膠細胞所引起的細胞死亡,且膽固醇不足會抑制細胞在回復期的增生能力。此外,甲羥戊酸的處理會抵銷膽固醇不足加劇麩胺酸對星狀神經膠細胞所引起的細胞死亡,證實 lovastatin 藉由抑制 3-hydroxy-3-methylglutaryl CoA reductase 的活性而增加星狀神經膠細胞的麩胺酸興奮性毒性。再者,先前的研究證實星狀神經膠細胞之細胞膜上的麩胺酸運輸體參與麩胺酸的興奮性毒性,所以我觀察膽固醇不足對於星狀神經膠細胞之麩胺酸運輸體的影響,首先利用細胞對 [3H]D-aspartate 的吸收量來測量麩胺酸運輸體的活性,發覺膽固醇不足的細胞對 [3H]D-aspartate 的吸收能力高於未經 lovastatin 與 b-cyclodextrin 處理的細胞,且在麩胺酸處理期間仍具有此特性,但這樣的結果仍無法證實此現象為膽固醇不足加劇麩胺酸對星狀神經膠細胞所引起之細胞死亡的機制。
此外,膽固醇不足不會影響海馬迴神經細胞的存活率,且不加劇麩胺酸對神經細胞所引起的細胞死亡。由此可知,本研究證實膽固醇不足加劇麩胺酸興奮性毒性的特性具有細胞種類的選擇性,也更進一步深究了膽固醇不足與細胞死亡的關係,使我們對於細胞種類間的特異性與腦部疾病的發展,具有多元化的見解。
英文摘要
Cholesterol, the main component of cell membrane, is essential for the physical ability of membrane and the function of protein on membrane. Recently, the research indicated that cholesterol deficiency is associated with aging and Alzheimer’s disease. Previous studies from this laboratory demonstrated that cholesterol deficiency aggravated glutamate (Glu)-induced cell death in the hippocampal neuron/glia mixed cultures. Because astrocytes and neurons are main groups in brain with different functions and metabolism, I used hippocampal astrocyte cultures and neuron-enriched cultures to delineate the cellular target(s) for the damaging effect of cholesterol deficiency.
A combination of lovastatin and b-cyclodextrin treatment reduced cellular cholesterol content while having no effect on the rate of cell proliferation and cell cycle in astrocyte cultures. In order to estimate cell death, I observed membrane damage and metabolic activity of cells via assaying the release of lactate dehydrogenase from damaging cells and the reduction of WST-1 reagent by living cells respectively. In astrocyte cultures treated with Glu for 6 hr followed by a recovery period of 8 hr, there was delayed membrane damage during the recovery period. Prolonging the incubation of Glu prolong to 12 hr induced cell death as indicated by cell membrane damage and defect in cellular metabolism. Cholesterol deficiency aggravated Glu-induced membrane damage and defect in metabolic activity in cultured astrocytes. On the other hand, cholesterol deficiency inhibited cell proliferation during the recovery period after the incubation of Glu for 12 hr. Because the administration of mevalonate reversed the damaging effect of cholesterol deficiency, it was suggested that the inhibition of activity of 3-hydroxy-3-methylglutaryl CoA reductase is involved in this phenomenon. As noted, the activity of Glu transporters is involved in excitotoxicity of astrocyte. In this regard, I tested the possibility that cholesterol deprivation might affect the uptake of Glu by astrocytes. Using [3H]D-aspartate as a tracer, I observed that cholesterol deficiency increased the activity of Glu transporter in cultured astrocytes. After Glu exposure, the uptake of [3H]D-aspartate in cholesterol-depleted astrocytes remained higher than those without the treatment of lovastatin and b-cyclodextrin.
And cholesterol deficiency didn’t affect cell viability and Glu-induced cell death in neuron-enriched cultures. Taken together, it was interesting that the damaging effect of cholesterol deficiency was dependent on different species of cells. And it provides us different concept on cell type and pathogenesis of brain disease.
目錄
中文摘要 -------------------------------------------------------- 1
英文摘要 -------------------------------------------------------- 2
緒論 -------------------------------------------------------------- 3
材料與方法
一、材料 -------------------------------------------------------- 15
二、方法
(一)海馬迴神經細胞培養之製備 ----------------------------- 15
(二)海馬迴星狀神經膠細胞培養之製備 ----------------------- 16
(三)降低海馬迴神經或星狀神經膠細胞培養的膽固醇含量 ----- 17
(四)麩胺酸誘發海馬迴神經或神經膠細胞培養之細胞死亡 ----- 18
(五)乳酸脫氫酶分析法 -------------------------------------- 18
(六)WST-1 分析法 ----------------------------------------- 19
(七)麩胺酸回收分析法 -------------------------------------- 19
(八)細胞膽固醇含量之測量 --------------------------------- 20
(九)細胞 DNA 合成之測試 --------------------------------- 21
(十)免疫細胞染色法 ----------------------------------------- 21
(十一)細胞週期之分析 --------------------------------------- 22
(十二)資料分析與統計方法 ----------------------------------- 22
結果 -------------------------------------------------------------- 23
討論 -------------------------------------------------------------- 32
參考文獻 -------------------------------------------------------- 38
圖表說明
Table 1. Lovastatin 與 β-cyclodextrin 的處理對海馬迴細胞
培養之細胞膜完整性與代謝活性的影響 -------------------- 50
Fig. 1. 海馬迴星狀神經膠細胞培養的細胞型態 ---------------------- 51
Fig. 2. 海馬迴星狀神經膠細胞培養的 LDH 酵素反應與
WST-1 還原能力 ----------------------------------------- 53
Fig. 3. Lovastatin 與 β-cyclodextrin 的處理降低海馬迴星狀神經膠細胞
內的膽固醇含量 ------------------------------------------ 54
Fig. 4. Lovastatin 單獨或與 mevalonate 同時處理,不會影響海馬迴星狀神
經膠細胞的增生能力 ------------------------------------- 55
Fig. 5. Lovastatin 及 b-cyclodextrin 單獨或與 mevalonate 共同處理,皆不
會影響海馬迴星狀神經膠細胞的細胞週期 ----------------- 56
Fig. 6. 膽固醇不足會加劇海馬迴星狀神經膠細胞因 Glu 處理 6 小時後所
見之細胞膜損傷 ----------------------------------------- 57
Fig. 7. 膽固醇不足不會影響經 Glu 處理 6 小時後,海馬迴星狀神經膠細
胞培養的代謝活性 --------------------------------------- 58
Fig. 8. 膽固醇不足會加劇海馬迴星狀神經膠細胞因 Glu 處理 12 小時後
所見之細胞膜損傷 --------------------------------------- 59
Fig. 9. 膽固醇不足加劇星狀神經膠細胞經 12 小時 Glu 處理所致代謝活
性之下降 ------------------------------------------------ 60
Fig. 10. Lovastatin 與 b-cyclodextrin 的處理會降低海馬迴星狀神經膠細胞
經 12 小時 Glu處理後於回復期的增生能力 -------------- 61
Fig. 11. 海馬迴星狀神經膠細胞上 Glu transporter 的特性 ----------- 62
Fig. 12. Lovastatin 與 b-cyclodextrin 的處理會增加海馬迴星狀神經膠細胞
對 D-Asp 的吸收能力 ----------------------------------- 63
Fig. 13. Lovastatin 與 b-cyclodextrin 的處理會增加星狀神經膠細胞在
Glu 處理時對 D-Asp 的吸收能力 ------------------------- 64
Fig. 14. Mevalonate 會回復 lovastatin 與 b-cyclodextrin 的處理對海馬迴
星狀神經膠細胞所引起的 LDH 含量下降 ---------------- 65
Fig. 15. Mevalonate 會抵銷 lovastatin 與 b-cyclodextrin 的處理所加劇
Glu 誘發海馬迴星狀神經膠細胞之細胞膜損傷 ------------ 66
Fig. 16. Mevalonate 會抵銷 lovastatin 與 b-cyclodextrin 的處理所加劇
Glu 誘發海馬迴星狀神經膠細胞之細胞代謝活性下降 ----- 67
Fig. 17. Lovastatin 與 b-cyclodextrin 的處理不會影響海馬迴神經細胞經
Glu 處理 6 小時後細胞膜的狀態 ------------------------- 68
Fig. 18. Lovastatin 與 b-cyclodextrin 的處理不會改變海馬迴神經細胞經
6 小時 Glu 處理後之胞代謝活性 ------------------------- 69
Fig. 19. Lovastatin 與 b-cyclodextrin 的處理不會影響海馬迴神經細胞經
Glu 處理 12 小時後所見之細胞膜損傷 -------------------- 70
Fig. 20. Lovastatin 與 b-cyclodextrin 的處理不會改變海馬迴神經細胞經
12 小時 Glu 處理所致之細胞代謝活性下降 --------------- 71
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林欣貝 (1999) 膽固醇對腦細胞死亡之影響. 國立陽明大學生理學研究所碩士論文
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