跳到主要內容

臺灣博碩士論文加值系統

(216.73.216.181) 您好!臺灣時間:2025/12/16 08:36
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:郭佳瑜
研究生(外文):Jia-Yu Kuo
論文名稱:Lovastatin在星狀神經膠細胞中調控Rho訊息傳遞之機制探討
論文名稱(外文):Mechanistic study of lovastatin modulating Rho GTPase signaling in astrocytes
指導教授:周韻家
指導教授(外文):Yun-Chia Chou
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:神經科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:97
語文別:中文
論文頁數:48
中文關鍵詞:海馬迴神經膠細胞細胞骨架阿茲海默氏症Rho蛋白質
外文關鍵詞:Hippocampal astrocyteActin cytoskeletonAlzheimer's diseaseRho protein
相關次數:
  • 被引用被引用:0
  • 點閱點閱:241
  • 評分評分:
  • 下載下載:39
  • 收藏至我的研究室書目清單書目收藏:0
Statin是HMG-CoA reductase的抑制劑,能抑制細胞中膽固醇的合成,常被用於治療高膽固醇血症。而最近的研究發現,statin也會影響神經系統。過去實驗室的研究發現,利用lovastatin合併β-cyclodextrin處理海馬迴星狀神經膠細胞,會造成海馬迴神經膠細胞長出process,並且改變了細胞的actin細胞骨架;但,這樣的處理,對於海馬迴神經細胞並沒有作用。因此,我進一步去探究,lovastatin所誘導的海馬迴星狀神經膠細胞,actin細胞骨架的改變是否透過RhoA蛋白質,以及lovastatin是否會影響海馬迴神經細胞RhoA的表現。我發現lovastatin會增加海馬迴星狀神經膠細胞RhoA的表現;但卻會抑制RhoA轉移到細胞膜上;另一方面,海馬迴神經細胞的RhoA則不受lovastatin的影響。
Statin is the inhibitor of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. It is commonly used to treat patients suffering from hypercholesterolemia. Recent studies have demonstrated that statin also has some effects on nervous system. Previous studies from this laboratory already found that the combined treatment of lovastatin and β-cyclodextrin induced the process outgrowth and actin cytoskeleton reorganization, namely decreased actin rings and actin filaments in hippocampal astrocytes. Nonetheless, it showed no similar effect on hippocampal neurons. It is known that Rho protein regulates the organization of actin cytoskeleton and the formation of actin filaments within cells. However, the mechanism by which lovastatin decreases actin filaments in hippocampal astrocytes is still unknown. In my study, I found that lovastatin increased the expression of RhoA but inhibited the translocation of RhoA to the plasma membrane. In contrast, lovastatin didn’t influence the expression of RhoA in hippocampal neurons.
目錄
英文摘要––––––––––––––––––––01
中文摘要––––––––––––––––––––02
序論––––––––––––––––––––––03
材料與方法–––––––––––––––––––10
結果––––––––––––––––––––––18
討論––––––––––––––––––––––20
文獻參考––––––––––––––––––––25
圖片與說明–––––––––––––––––––35
附錄––––––––––––––––––––––44
Abe K., Misawa M. (2003) Astrocyte stellation induced by Rho kinase inhibitors in culture. Dev. Brain Res. 143:99-104.

Arvanitakis Z, Schneider JA, Wilson RS, Bienias JL, Kelly JF, Evans DA, Bennett DA. (2008) Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology. 70:1795-1802.

Ballabh P., Braun A., Nedergaard M. (2004) The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol. Dis. 16:1-13.

Bustelo X.R., Sauzeau V., Berenjeno I.M. (2007) GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays. 29:356-370.

Chan C.C., Wong A.K., Liu J., Steeves J.D., Tetzlaff W. (2007) ROCK inhibition with Y27632 activates astrocytes and increases their expression of neurite growth-inhibitory chondroitin sulfate proteoglycans. Glia 55:369-384.

Chartier-Harlin M.C., Parfitt M., Legrain S., Pérez-Tur J., Brousseau T., Evans A., Berr C., Vidal O., Roques P., Gourlet V., Fruchart J.C., Delacourte A., Rossor M., Amouye P. (1994) Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum. Mol. Genet. 3:569-574.

Chattopadhyay A., Paila Y.D. (2007) Lipid–protein interactions, regulation and dysfunction of brain cholesterol. Biochem. Biophys. Res. Commun. 354:627-633.

Chen C.J., Ou Y.C., Lin S.Y., Liao S.L., Huang Y.S., Chiang A.N. (2006) L-glutamate activates RhoA GTPase leading to suppression of astrocyte stellation. Eur. J. Neurosci. 23:1977-1987.

Chou Y.C. (1998) Corticosterone exacerbates cyanide-induced cell death in hippocampal cultures: role of astrocytes. Neurochem. Int. 32:219-226.

Chou Y.C., Lin S.B., Tsai L.H., Tsai H.I., Lin C.M. (2003) Cholesterol deficiency increases the vulnerability of hippocampal glia in primary culture to glutamate-induced excitotoxicity. Neurochem. Int. 43:197-209.

Cordle A., Koenigsknecht-Talboo J., Wilkinson B., Limpert A., Landreth G. (2005) Mechanisms of statin-mediated inhibition of small G-protein function. J. Biol. Chem. 280:34202-34209.

Dremina E.S., Sharov V.S., Schöneich C. (2005) Protein tyrosine nitration in rat brain is associated with raft proteins, flotillin-1 and alpha-tubulin: effect of biological aging. J. Neurochem. 93:1262-1271.

DeWitt D.A., Perry G., Cohen M., Doller C., Silver J. (1998) Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease. Exp. Neurol. 149:329-340.

Dunford J.E., Rogers M.J., Ebetino F.H., Phipps R.J., Coxon F.P. (2006) Inhibition of protein prenylation by bisphosphonates causes sustained activation of Rac, Cdc42, and Rho GTPases. J. Bone Miner. Res. 21:684-694.

Escartin C., Brouillet E., Gubellini P., Trioulier Y., Jacquard C., Smadja C., Knott G.W., Kerkerian-Le Goff L., Déglon N., Hantraye P., Bonvento G. (2006) Ciliary neurotrophic factor activates astrocytes, redistributes their glutamate transporters GLAST and GLT-1 to raft microdomains, and improves glutamate handling in vivo. J. Neurosci. 26:5978-5989.

Fassbender K., Simons M., Bergmann C., Stroick M., Lutjohann D., Keller P., Runz H., Kuhl S., Bertsch T., von Bergmann K., Hennerici M., Beyreuther K., Hartmann T. (2001) Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 98:5856-5861.

Fujisawa K., Fujita A., Ishizaki T., Saito Y., Narumiya S. (1996) Identification of the Rho-binding domain of p160ROCK, a Rho-associated coiled-coil containing protein kinase. J. Biol. Chem. 271:23022-23028.

Gegelashvili G., Dehnes Y., Danbolt N.C., Schousboe A. (2000) The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms. Neurochem. Int. 237:163-170.

Gorovoy M., Neamu R., Niu J., Vogel S., Predescu D., Miyoshi J., Takai Y., Kini V., Mehta D., Malik A.B., Voyno-Yasenetskaya T. (2007) RhoGDI-1 modulation of the activity of monomeric RhoGTPase RhoA regulates endothelial barrier function in mouse lungs. Circ. Res. 101:50-58.

Hall A. (1998) Rho GTPases and the actin cytoskeleton. Science 279:509-514.

Hancock J.F., Hall A. (1993) A novel role for RhoGDI as an inhibitor of GAP proteins.
EMBO J. 12:1915-1921.

Hartmann T., Kuchenbecker J. and Grimm M.O.W. (2007) Alzheimer’s disease: the lipid connection. J. Neurochem. 103:159-170.

Hart M.J., Eva A., Evans T., Aaronson S.A., Cerione R.A. (1991) Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbl oncogene product. Nature 354:311-314.

Heredia L., Helguera P., de Olmos S., Kedikian G., Solá Vigo F., LaFerla F., Staufenbiel M., de Olmos J., Busciglio J., Cáceres A., Lorenzo A. (2006 ) Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid β-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer’s disease. J. Neurosci. 26:6533-6542.

Hillyard D.Z., Nutt C.D., Thomson J., McDonald K.J., Wan R.K., Cameron A.J., Mark P.B., Jardine A.G. (2007) Statins inhibit NK cell cytotoxicity by membrane raft depletion rather than inhibition of isoprenylation. Atherosclerosis 191:319-325.

Holstein S.A., Wohlford-Lenane C.L., Hohl R.J. (2002) Consequences of mevalonate depletion. Differential transcriptional, translational, and post-translational up-regulation of Ras, Rap1a, RhoA, and RhoB. J. Biol. Chem. 277:10678-10682.

Höltje M., Hoffmann A., Hofmann F., Mucke C., Grosse G., Van Rooijen N., Kettenmann H., Just I., Ahnert-Hilger G. (2005) Role of Rho GTPase in astrocyte morphology and migratory response during in vitro wound healing. J. Neurochem. 95:1237-1248.

Hu J., Akama K.T., Krafft G.A., Chromy B.A., Van Eldik L.J. (1998) Amyloid-beta peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release. Brain Res. 785:195-206.

Kim Y.K., Lee H.J., Kim J.Y., Yoon D.K., Choi S.H., Lee M.S. (2002) Low serum cholesterol is correlated to suicidality in a Korean sample. Acta. Psychiatr. Scand. 105:141-148.

Kirsch C., Eckert G.P., Mueller W.E. (2003) Statin effects on cholesterol micro-domains in brain plasma membranes. Biochem. Pharmacol. 65:843-856.

Kivipelto M., Helkala E., Laakso M.P., Hänninen T., Hallikainen M., Alhainen K., Soininen H., Tuomilehto J., Nissien A. (2001) Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. Br. Med. J. 322:1447-1451.

La Ville A., Moshy R., Turner P.R., Miller N.E., Lewis B. (1984) Inhibition of cholesterol synthesis reduces low-density-lipoprotein apoprotein B production without decreasing very-low-density-lipoprotein apoprotein B synthesis in rabbits. Biochem. J. 219:321-323.

Lange Y. (1991) Disposition of intracellular cholesterol in human fibroblasts. J. Lipid. Res. 32:329-339.
Lee M.H., Cho Y.S., Han Y.M. (2007) Simvastatin suppresses self-renewal of mouse embryonic stem cells by inhibiting RhoA geranylgeranylation. Stem Cells. 25:1654-1663.

Leung T., Manser E., Tan L., Lim L. (1995) A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J. Biol. Chem. 270:29051-29054.

Maddala R.L., Reddy V.N., Rao P.V. (2001) Lovastatin-induced cytoskeletal reorganization in lens epithelial cells: role of Rho GTPases. Invest. Ophthalmol. Vis. Sci. 42:2610-2615.

Masters C.L., Cappai R., Barnham K.J., and Villemagne V.L. (2006) Molecular mechanisms for Alzheimer’s disease : implications for neuroimaging and therapeutics. J. Neurochem. 97:1700-1725.

Mauch D.H., Nagler K., Schumacher S., Goritz C., Muller E., Otto A., Pfrieger F.W. (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354-1357.

McKeon R.J., Schreiber R.C., Rudge J.S., Silver J. (1991) Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J. Neurosci. 11:3398-3411.

Meng Y., Takahashi H., Meng J., Zhang Y., Lu G., Asrar S., Nakamura T., Jia Z. (2004) Regulation of ADF/cofilin phosphorylation and synaptic function by LIM-kinase. Neuropharmacology 47:746-754.

Meske V., Albert F., Richter D., Schwarze J., Ohm T.G. (2003) Blockade of HMG-CoA reductase activity causes changes in microtubule-stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease. Eur. J. Neurosci. 17:93-102.

Michaely P.A., Mineo C., Ying Y.S., Anderson R.G. (1999) Polarized distribution of endogenous Rac1 and RhoA at the cell surface. J. Biol. Chem. 274:21430-21436.

Miñambres R., Guasch R.M., Perez-Aragó A., Guerri C. (2006) The RhoA/ROCK-I/MLC pathway is involved in the ethanol-induced apoptosis by anoikis in astrocytes. J. Cell Sci. 119:271-282.

Nakamura H.;MEGA Study Group. (2007) Primary prevention of cardiovascular diseases among hypercholesterolemic Japanese with a low dose of pravastatin. Atheroscler. Suppl. 8:13-17.

Nobes C.D., Hall A. (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81:53-62.

Nakagawa O., Fujisawa K., Ishizaki T., Saito Y., Nakao K., Narumiya S. (1996) ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett. 392:189-193.

Orita S., Kaibuchi K., Kuroda S., Shimizu K., Nakanishi H., Takai Y. (1993) Comparison of kinetic properties between two mammalian ras p21 GDP/GTP exchange proteins, ras guanine nucleotide-releasing factor and smg GDP dissociation stimulation. J. Biol. Chem. 268:25542-25546.

Pfrieger F.W. (2003) Role of cholesterol in synapse formation and function. Biochim. Biophys. Acta. 1610:271-280.

Pucadyil T.J., Chattopadhyay A. (2004) Cholesterol modulates ligand binding and G-protein coupling to serotonin1A receptors from bovine hippocampus. Biochim. Biophys. Acta. 1663:188-200.

Pihlaja R., Koistinaho J., Malm T., Sikkilä H., Vainio S., Koistinaho M. (2008) Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer's disease. Glia 56:154-163.

Roberts P.J., Mitin N., Keller P.J., Chenette E.J., Madigan J.P., Currin R.O., Cox A.D., Wilson O., Kirschmeier P., Der C.J. (2008) Rho family GTPase modification and dependence on CAAX motif-signaled posttranslational modification. J. Biol. Chem. (In press )

Scheffzek K., Ahmadian M.R., Kabsch W., Wiesmüller L., Lautwein A., Schmitz F., Wittinghofer A. (1997) The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277:333-338.

Schiera G., Sala S., Gallo A., Raffa M.P., Pitarresi G.L., Savettieri G., Di Liegro I. (2005) Permeability properties of a three-cell type in vitro model of blood-brain barrier. J. Cell. Mol. Med. 9:373-379.

Shin J.Y., Fang Z.H., Yu Z.X., Wang C.E., Li S.H., Li X.J. (2005) Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J. Cell Biol. 171:1001-1012.
Solski P.A., Helms W., Keely P.J., Su L., Der C.J. (2002) RhoA biological activity is dependent on prenylation but independent of specific isoprenoid modification. Cell Growth Differ. 13:363-373.

Simons K., Ikonen E. (1997) Functional rafts in cell membranes. Nature 387:569-572.

Solà C., Casal C., Tusell J.M., Serratosa J. (2002) Astrocytes enhance lipopolysaccharide-induced nitric oxide production by microglial cells. Eur. J. Neurosci. 16:1275-1283.

Sumi T., Matsumoto K., Takai Y., and Nakamura T. (1999) Cofilin phosphorylation and actin cytoskeletal dynamics regulated by Rho- and Cdc42-activated LIM-kinase 2. J. Cell. Biol. 147:1519-1532.

Takai Y., Sasaki T., Matozaki T. (2001) Small GTP-binding proteins. Physiol. Rev. 81:153-208.

Takeda N., Kondo M., Ito S., Ito Y., Shimokata K., Kume H. (2006) Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin. Am. J. Respir. Cell Mol. Biol. 35:722-729.

Tobert J.A. (2003) Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat. Rev. 2:517-526.

Tsai H.I., Tsai L.H., Chen M.Y., Chou Y.C. (2006) Cholesterol deficiency perturbs actin signaling and glutamate homeostasis in hippocampal astrocytes. Brain Res. 1104:27-38.

Turner S.J., Zhuang S., Zhang T., Boss G.R., Pilz R.B. (2008) Effects of lovastatin on Rho isoform expression, activity, and association with guanine nucleotide dissociation inhibitors. Biochem. Pharmacol. 75:405-413.

Vandevord P.J., Leung L.Y., Hardy W., Mason M., Yang K.H., King A.I. (2008) Up-regulation of reactivity and survival genes in astrocytes after exposure to short duration overpressure. Neurosci. Lett. 434:247-252.

Xu F., Vitek M.P., Colton C.A., Previti M.L., Gharkholonarehe N., Davis J., Van Nostrand W.E. (2008) Human apolipoprotein E redistributes fibrillar amyloid deposition in Tg-SwDI mice. J. Neurosci. 28:5312-5320.

Zeidan A., Javadov S., Karmazyn M. (2006) Essential role of Rho/ROCK-dependent processes and actin dynamics in mediating leptin-induced hypertrophy in rat neonatal ventricular myocytes. Cardiovasc. Res. 72:101-111.

蔡弘毅(2004) 膽固醇短缺加劇海馬迴星狀神經膠細胞因麩胺酸所誘發細胞死亡之機制探討。國立陽明大學神經科學研究所碩士論文
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top