2000 年度実績報告書

神経回路網の形成・成熟・老化・病的過程におけるアポトーシス制御分子の役割

研究課題

研究課題/領域番号	12053242
研究機関	京都大学
研究代表者	下濱俊京都大学, 医学研究科, 講師 (60235687)
キーワード	発生 / 神経回路網 / 老化 / アポトーシス / カスペース / Bcl-2 / アルツハイマー病 / 神経終末
研究概要	個体の発生過程においてはアポトーシスによって臓器の形態形成、不要構造の除去、細胞数の調整、異常なあるいは有害な細胞の除去などが行なわれることがわかってきたが、脳の形成・成熟・老化の過程でアポトーシス調節分子がどのように制御され、神経回路網の発達・維持に関与しているかは殆どわかっていない。本研究では、神経回路網の形成・成熟・老化および病的過程におけるアポトーシス制御分子の役割について解析した。胎仔から生後2年までのWistarラットを用いた研究で、神経回路網の形成・成熟・老化に伴い、脳内Bcl-2ファミリー及びcaspaseファミリータンパク質の発現がそれぞれ特異的に制御されていること、また、興味あることに、神経回路網が大きく破綻し、高度の痴呆を呈するアルツハイマー病脳では脳の発生・生後発達期のアポトーシスが盛んな神経回路網が形成される時期と同様に、caspase-3,Bak,Bad,Bcl-2などのアポートーシス関連分子の発現を増大させる機構が作動していることが示唆された。また、8週齢のラット脳より核、ミエリン分画、神経終末、ミトコンドリア、ミクロゾーム、可溶性分画の細胞分画を調整した。各分画でのcaspaseの分布を免疫化学的に半定量的に解析すると、caspase-2、caspase-3、caspase-6、caspase-9、Apaf-1などは、神経終末分画にも多く存在しており、シナプス可塑性機構に関与していることが示唆された。

研究成果
(18件)

すべてその他

すべて文献書誌 (18件)

[文献書誌] Kume T,Nishikawa.H et al: "P75-mediated neuroprotection by NGF against glutamate cytotoxiclity in cortical cultures"Brain Research. 852. 279-289 (2000)
[文献書誌] Kageyama T,Oeda T. et al: "Coexistence of expanded CAG repeats in the MJDla and DRPLA genes"Neurology. 54. 265-266 (2000)
[文献書誌] Yawamoto K,Hashimoto K et al: "An IPs-assisted form of Ca^<2+>-induced Ca^<2+> release in neocortical neurons"Neuroreport. 11. 535-539 (2000)
[文献書誌] Sawada H,Ibi,M et al: "Neuroprotective mechanism of glial cell line-derived neurotrophic tactor in mesercephalic neurons"Journal of Neurochemistry. 74. 1175-1184 (2000)
[文献書誌] Honda K,Sawada H et al: "Phosphatidylinositol 3-kinase mediates neuroprotection by estrogen in cultured cortical neurons"Journal of Neuroscience Research. 60. 321-327 (2000)
[文献書誌] Sawada H,Ibi M et al: "Mechanisms of antiapoptotic effects of estrogen in nigral dopaminergic neurons"FASEB Journal. 14. 1202-1214 (2000)
[文献書誌] Tanino H,Shimohama S et al: "Increase in phospholipose C-δ_1 protein levels in aluminum-treated rat brains"Biochem Biophys Res Commun. 271. 620-625 (2000)
[文献書誌] Shimohama S,Tanino H et al: "Activation of NADPH oxidase in Alzheimer's disease brains"Biochem Biophys Res Commun. 273. 5-9 (2000)
[文献書誌] Urushitani M,Inoeu R et al: "Neuroprotective effect of cyclin GMP against radical-induced toxicity in cultured spinal motor neurons"Journal of Neuro science Research. 61. 443-448 (2000)
[文献書誌] Kageyama T,Nakamura M et al: "The 4F2hc/CAT1 complex transports L-Dopa across the blood-brain barrier"Brain Research. 879. 115-121 (2000)
[文献書誌] Imura T,Shimohama S: "Opposing effects of adenosiue on the survival of glial cells exposed to chemical ischemia"Journal of Neuroscience Research. 62. 539-546 (2000)
[文献書誌] Nakanizo T,Urushitani M et al: "Protection of motor neurons by estradiol"Neuro report. 11. 3493-3497 (2000)
[文献書誌] Kakimara J.Kitamura Y et al: "Bip/GRP78-induced protection of cytokines and uptake of amyloid-β(1-42) peptide in microglia"Biochem Biophys Res Commun. 281. 6-10 (2001)
[文献書誌] Kageyama T,Imura T et al: "Distribution of the 4F2 light chain, LAT1, in the mouse brain"Neuroreport. 11. 3663-3666 (2000)
[文献書誌] Urashitani M,Nakamizo T et al: "NMDA receptor-mediated mitochoudrical Ca^<2+> overload in acute extitotoxic motor neurons death : a distinct mechanism from chronic neurotoxicity after Ca^<2+> influx"Journal of Neuroscience Research. 63. 377-387 (2001)
[文献書誌] Shimohamas,Kihara T: "Nicotinic receptor-mediated protection against beta amyloid neurotoxicity"Biological Psychiatry. (in press). (2001)
[文献書誌] Kihara T,Shimohama S et al: "Alpha 7 nicotinic receptor transduces signals to PT3 kinase to block AB-induced neurotoxicity"Journal of Biological Chemistry. (in press). (2001)
[文献書誌] Honda K,Shimohama S et al: "Nongeneric antiapoptotic signal transduction by estrogen in cultured cortical neurons"Journal of Neuroscience Research. (in press). (2001)

2000 年度 実績報告書

神経回路網の形成・成熟・老化・病的過程におけるアポトーシス制御分子の役割

研究代表者

下濱 俊 京都大学, 医学研究科, 講師 (60235687)

研究成果

[文献書誌] Kume T,Nishikawa.H et al: "P75-mediated neuroprotection by NGF against glutamate cytotoxiclity in cortical cultures"Brain Research. 852. 279-289 (2000)

[文献書誌] Kageyama T,Oeda T. et al: "Coexistence of expanded CAG repeats in the MJDla and DRPLA genes"Neurology. 54. 265-266 (2000)

[文献書誌] Yawamoto K,Hashimoto K et al: "An IPs-assisted form of Ca^<2+>-induced Ca^<2+> release in neocortical neurons"Neuroreport. 11. 535-539 (2000)

[文献書誌] Sawada H,Ibi,M et al: "Neuroprotective mechanism of glial cell line-derived neurotrophic tactor in mesercephalic neurons"Journal of Neurochemistry. 74. 1175-1184 (2000)

[文献書誌] Honda K,Sawada H et al: "Phosphatidylinositol 3-kinase mediates neuroprotection by estrogen in cultured cortical neurons"Journal of Neuroscience Research. 60. 321-327 (2000)

[文献書誌] Sawada H,Ibi M et al: "Mechanisms of antiapoptotic effects of estrogen in nigral dopaminergic neurons"FASEB Journal. 14. 1202-1214 (2000)

[文献書誌] Tanino H,Shimohama S et al: "Increase in phospholipose C-δ_1 protein levels in aluminum-treated rat brains"Biochem Biophys Res Commun. 271. 620-625 (2000)

[文献書誌] Shimohama S,Tanino H et al: "Activation of NADPH oxidase in Alzheimer's disease brains"Biochem Biophys Res Commun. 273. 5-9 (2000)

[文献書誌] Urushitani M,Inoeu R et al: "Neuroprotective effect of cyclin GMP against radical-induced toxicity in cultured spinal motor neurons"Journal of Neuro science Research. 61. 443-448 (2000)

[文献書誌] Kageyama T,Nakamura M et al: "The 4F2hc/CAT1 complex transports L-Dopa across the blood-brain barrier"Brain Research. 879. 115-121 (2000)

[文献書誌] Imura T,Shimohama S: "Opposing effects of adenosiue on the survival of glial cells exposed to chemical ischemia"Journal of Neuroscience Research. 62. 539-546 (2000)

[文献書誌] Nakanizo T,Urushitani M et al: "Protection of motor neurons by estradiol"Neuro report. 11. 3493-3497 (2000)

[文献書誌] Kakimara J.Kitamura Y et al: "Bip/GRP78-induced protection of cytokines and uptake of amyloid-β(1-42) peptide in microglia"Biochem Biophys Res Commun. 281. 6-10 (2001)

[文献書誌] Kageyama T,Imura T et al: "Distribution of the 4F2 light chain, LAT1, in the mouse brain"Neuroreport. 11. 3663-3666 (2000)

[文献書誌] Urashitani M,Nakamizo T et al: "NMDA receptor-mediated mitochoudrical Ca^<2+> overload in acute extitotoxic motor neurons death : a distinct mechanism from chronic neurotoxicity after Ca^<2+> influx"Journal of Neuroscience Research. 63. 377-387 (2001)

[文献書誌] Shimohamas,Kihara T: "Nicotinic receptor-mediated protection against beta amyloid neurotoxicity"Biological Psychiatry. (in press). (2001)

[文献書誌] Kihara T,Shimohama S et al: "Alpha 7 nicotinic receptor transduces signals to PT3 kinase to block AB-induced neurotoxicity"Journal of Biological Chemistry. (in press). (2001)

[文献書誌] Honda K,Shimohama S et al: "Nongeneric antiapoptotic signal transduction by estrogen in cultured cortical neurons"Journal of Neuroscience Research. (in press). (2001)

2000 年度実績報告書

下濱俊京都大学, 医学研究科, 講師 (60235687)