Analysis of the relationship between Amyloid β protein and cholesterol in Alzheimer's disease.

阿尔茨海默病β淀粉样蛋白与胆固醇的关系分析。

基本信息

项目摘要

Alzheimer's disease (AD) is one of the most frequent neurodegenerative disorders in elder people. Familial AD is known to be caused by mutations in the amyloid β protein precursor (APP), Presenilin 1 or 2, though these causes of AD are relatively uncommon. But those genetic risk factors account for less than 2% of all AD causes, remaining are sporadic AD.Amyloid β protein (Aβ) is one of the abnormally accumulated proteins in AD's brain. Aβ fibril formation and deposition long have been linked to the neuropathogenesis of AD. And abnormal processing of APP and increase in Aβ may play a major role in the pathogenesis of the hereditary forms and also that of sporadic AD.We investigate the relationship between APP, Aβ and cholesterol to find the evidence that cholesterol may play a role in the cleavage of APP. We made APP-overexpressed CHO cells and npc1 defected CHO (nCHO) cells by transfect the wild type, Swedish and Tottori (D678N) type mutated APP. Npc1 is defected in Niemann-Pick disease type C, which has lack in intracellular transport and maintenance of homeostasis of cholesterol. We analyzed intracellular quantity, synthesis and esterification of cholesterol, but excess APP had no effects directly. Then we determined intracellular APP levels and production Aβ in different intracellular cholesterol background using both cells with extracellular stimulation of Aluminum, LDL and oxidative stress.Despite no relationship APP, Aβ and Aluminum, more sensitive against Aluminum in nCHO cells compared normal cells. Exposure of excess LDL induced the cleavage of APP by β-secretase in nCHO cells, which indicated Aβ production. Intracellular APP levels on the oxidative stress were decreased in CHO cells but not affected in nCHO. Fewer lipids in nCHO of membrane in nCHO may prevent the oxidative attack against cell membrane.The disruption of cholesterol homeostasis might accelerate and strengthen the risks in AD.
阿尔茨海默病(Alzheimer's disease,AD)是老年人最常见的神经退行性疾病之一。已知家族性AD是由淀粉样β蛋白前体(APP)早老素1或2的突变引起的,尽管AD的这些原因相对罕见。但这些遗传因素仅占AD病因的不到2%,其余为散发性AD。淀粉样β蛋白(Amyloid β protein,Aβ)是AD患者脑内异常聚集的蛋白质之一。长期以来,Aβ原纤维的形成和沉积与AD的神经发病机制有关。本研究通过研究APP、Aβ与胆固醇之间的关系,寻找胆固醇参与APP裂解的证据。瑞典和鸟取(D 678 N)型突变的APP。Npc 1在C型尼曼-皮克病中有缺陷,该疾病缺乏胆固醇的细胞内转运和稳态维持。分析了细胞内胆固醇的含量、合成及酯化反应,但过量APP对胆固醇的合成无直接影响。然后,我们用铝、低密度脂蛋白(LDL)和氧化应激刺激两种细胞,在不同的细胞内胆固醇背景下,测定细胞内APP水平和Aβ的产生,尽管APP、Aβ与铝无关,但nCHO细胞对铝的敏感性高于正常细胞。在nCHO细胞中,过量LDL暴露诱导β-分泌酶切割APP,这表明Aβ产生。在CHO细胞中,氧化应激引起的细胞内APP水平降低,但在nCHO中不受影响。nCHO中膜脂的减少可能阻止了细胞膜的氧化攻击,胆固醇稳态的破坏可能加速和加强AD的风险。

项目成果

期刊论文数量(46)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Watanabe Y, Shimizu Y, Urakami K, Matsushima E, Nakashima K: "Vertical ophthalmoplegia in a demented patient with striato pallidodentate calcification"Psychiatry Clin.Neurosci.. 57・4. 447-450 (2003)
渡边 Y、清水 Y、浦上 K、松岛 E、中岛 K:“伴有纹状体苍白齿状钙化的痴呆患者的垂直眼肌麻痹”精神病学临床.神经科学.. 57・450 (2003)
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Wakutani Y, Kowa H, Kusumi M, Nakaso K, Yasui K, Wada-Isoe K, Urakami K, et al.: "The regulatory region polymorphisms of the MTHFR gene are not associated with Alzheimer's disease"Dement.Geriatr.Cogn.Disord.. 17・3. 147-150 (2004)
Wakutani Y、Kowa H、Kusumi M、Nakaso K、Yasui K、Wada-Isoe K、Urakami K 等人:“MTHFR 基因的调控区多态性与阿尔茨海默病无关”Dement.Geriatr.Cogn.Disord .. 17・3. 147-150 (2004)
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A novel presenilin 1 mutation (Y154N) in a patient with early onset Alzheimer's disease with spastic paraparesis
患有痉挛性截瘫的早发性阿尔茨海默病患者中发现一种新的早老素 1 突变 (Y154N)
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    2004
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  • 作者:
    Hattori H;Sakuma K;Wakutani Y;Wada K;Shimoda M;Urakami K;Kowa H;Nakashima K
  • 通讯作者:
    Nakashima K
浦上克哉, 谷口美也子: "アルツハイマー病に対するその他の治療の試みの現況"老年精神医学雑誌. 14・5. 567-569 (2003)
Katsuya Urakami、Miyako Taniguchi:“阿尔茨海默病其他治疗尝试的现状”《老年精神病学杂志》14・5(2003 年)。
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Wakutani Y, Watanabe K, Adachi Y, Isoe-Wada K, Urakami K, et al.: "Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer's disease"J.Neurol.Neurosurg.Psychiatr.. (in press). (2004)
Wakutani Y、Watanabe K、Adachi Y、Isoe-Wada K、Urakami K 等人:“可能的家族性阿尔茨海默病中的新型淀粉样前体蛋白基因错义突变 (D678N)”J.Neurol.Neurosurg.Psychiatr..(出版中)
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URAKAMI Katsuya其他文献

URAKAMI Katsuya的其他文献

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{{ truncateString('URAKAMI Katsuya', 18)}}的其他基金

Dementia Prevention - Early Detection by Olfactory Function Test and Prevention by Aromatherapy
预防认知障碍 - 嗅觉功能测试及早发现及芳香疗法预防
  • 批准号:
    20K07886
  • 财政年份:
    2020
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The analysis of altered glycosylation in Alzheimer's disease
阿尔茨海默氏病糖基化改变的分析
  • 批准号:
    22590933
  • 财政年份:
    2010
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Clinical utilization of β-Acl, newly identified Aβ associated protein, as a novel diagnostic marker of Alzheimer's disease.
β-Acl(新鉴定的 Aβ 相关蛋白)作为阿尔茨海默病的新型诊断标志物的临床应用。
  • 批准号:
    18590940
  • 财政年份:
    2006
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Abnormality of free radical scavenging mechanism in skin fibroblasts with dementia of the Alzheimer type
阿尔茨海默型痴呆皮肤成纤维细胞自由基清除机制异常
  • 批准号:
    05670558
  • 财政年份:
    1993
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)
Superoxide dismutase 1 in patients with dementia of the Alzheimer type.
阿尔茨海默型痴呆患者的超氧化物歧化酶 1。
  • 批准号:
    02670358
  • 财政年份:
    1990
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)
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