Analyses on oxidative stress and amyloid β protein in brains of mice with modified apolipoprotein E gene

载脂蛋白E基因修饰小鼠脑内氧化应激及β淀粉样蛋白分析

• 批准号: 18590924
• 负责人: TAMAOKA Akira
• 金额: $ 2.49万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590924/
• 关键词: Alzheimer's disease; apolipoprotein E; amyloid β protein; oxidative stress; hypoperfusion; lipid raft; konck-out mouse; knock-in mouse; 老化; ストレス; 痴呆; 脳神経疾患; 内科

Alzheimer's disease (AD) is characterized by the extensive deposition of amyloid β protein (Aβ) in brain cortex. Aβ generation reveals to be induced by oxidative stress, and Aβ is reported to evoke oxidative stress through generating reactive oxygen species, etc. In addition, apolipoprotein E (apoE)-ε4 genotype, one of the most powerful risk factors for all types of AD, has been elucidated in vitro to show less anti-oxidant effect than apoE-ε3 genotype. We have already shown that temporal cortices from patients with AD carrying apoE-ε4 homotypes contained more thiobarbituric acid-reactive substances (TBARS) than those carrying ε3 homotypes, suggesting that the lower antioxidant activity of apoe-E4 could contribute to its association with AD.We first measured TBARS in brains from apoE-knockout and wild type mice, elucidating that the former showed significantly more TBARS than the latter, suggesting antioxidant activities of apoE. We measured then TBARS in brains from human apoE3-knockin and apoE4-knockin mice, revealing that no differences in whole brain homogenates, but more TBARS with no significance in purified lipid raft fractions from apoE4-knockin than those from apoE3-knockin mice.We further investigated effects of chronic hypoperfusion on rat brains by bilateral carotid artery occlusions (BCAO). Both Aβ40 and Aβ42 were more increased in BCAO rat brains than those from sham-operated rats employed as controls. Immunocytochemical studies showed more expression of BACE1 than controls. Taking all these findings together in consideration, chronic hypoperfusion could induce BACE1 expression facilitating AD-deposion, the mechanism of which might be partly by evoking oxidative stress.Further studies are necessary to clarify the pathomechanism by which apoE-64 could be risk for AD and its relations to oxidative stress and Aβ generation.

阿尔茨海默病（Alzheimer's disease，AD）是以β淀粉样蛋白（amyloid β protein，Aβ）在大脑皮质广泛沉积为特征的疾病。Aβ的产生是由氧化应激诱导的，有报道称Aβ通过产生活性氧等引起氧化应激。此外，载脂蛋白E（apoE）-ε4基因型是所有类型AD最强的危险因素之一，其体外抗氧化作用弱于apoE-ε3基因型。我们已经表明，携带apoE-ε4同型的AD患者的颞叶皮质比携带ε3同型的患者含有更多的硫代巴比妥酸反应物质（TBARS），这表明apoE-E4的抗氧化活性较低可能有助于其与AD的相关性。我们首先测量了apoE敲除小鼠和野生型小鼠脑中的TBARS，阐明前者比后者显示出显著更多的TBARS，提示apoE具有抗氧化活性。然后我们测定了人apoE 3基因敲入小鼠和apoE 4基因敲入小鼠脑组织中的TBARS，结果表明，在全脑匀浆中没有差异，但在纯化的脂筏组分中，apoE 4基因敲入小鼠的TBARS比apoE 3基因敲入小鼠的多，但没有显著性差异。BCAO大鼠脑内Aβ40和Aβ42含量均高于假手术对照组。免疫细胞化学研究显示BACE 1的表达高于对照组。结论：慢性低灌注可诱导BACE 1表达，促进AD沉积，其机制可能与氧化应激有关，apoE-64与AD的发病机制及其与氧化应激和Aβ生成的关系有待进一步研究。

项目成果

アポEとAlzheime病-アポEの分子病態と疾患発症機構.別冊・医学のあゆみAlzheimer病-基礎・臨床研究の最新動向(岩坪威編集)

ApoE 与阿尔茨海默病 - ApoE 的分子病理学和疾病发病机制。另册：医学史阿尔茨海默病 - 基础和临床研究的最新趋势（岩坪武主编）。

• 发表时间: 2007
• 作者: 澤井摂(千葉大学 医学部神経内科);梅村啓史;森雅裕;佐藤守;小寺義男;朝長毅;野村文夫;桑原聡;玉岡晃
• 通讯作者: 玉岡晃

アポEとAlzheimer病-アポEの分子病態と疾患発症機構.別冊・医学のあゆみAlzheimer病-基礎・臨床研究の最新動向(岩坪 威編集)

ApoE 与阿尔茨海默病 - ApoE 的分子病理学和疾病发病机制。单独卷：病史阿尔茨海默病 - 基础和临床研究的最新趋势（岩坪武主编）。

• 发表时间: 2007
• 作者: 磯瀬沙希里;三澤園子;澁谷和幹;澤井摂;金井数明;森雅裕;桑原聡;国分則人;平田幸一;玉岡 晃
• 通讯作者: 玉岡 晃

Sodium channel beta4 ubunit : down-regulation and possible involvement in neuritic degeneration in Huntington' s disease transgenic mice

钠通道β4亚单位：下调并可能参与亨廷顿病转基因小鼠的神经炎变性

• 发表时间: 2006
• 期刊: J Neurochem 98・2
• 作者: Kuwabara S;Misawa S;Mori M,Tamura N;Kubota M;Hattori T;Nakamagoe K;Oyama F
• 通讯作者: Oyama F

認知症の分子病態の多様性

痴呆分子病理学的多样性

• 发表时间: 2006
• 期刊: 最新医学 61・12
• 作者: 森雅裕;桑原聡;早川省;金坂俊秀;服部孝道;玉岡 晃
• 通讯作者: 玉岡 晃

Familial Danish dementia: co-existence of Danish and Alzheimer amyloid subunits (ADan AND A{beta}) in the absence of compact plaques.

家族性丹麦痴呆：丹麦淀粉样蛋白亚基和阿尔茨海默淀粉样蛋白亚基（ADan 和 A{β}）在没有致密斑块的情况下共存。

• DOI: 10.1074/jbc.m504038200
• 发表时间: 2005
• 期刊: The Journal of biological chemistry
• 作者: Tomidokoro,Yasushi;Lashley,Tammaryn;Rostagno,Agueda;Neubert,ThomasA;Bojsen-Møller,Marie;Braendgaard,Hans;Plant,Gordon;Holton,Janice;Frangione,Blas;Révész,Tamas;Ghiso,Jorge
• 通讯作者: Ghiso,Jorge