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首页> 外文期刊>Nature >A mutation in APP protects against Alzheimer's disease and age-related cognitive decline
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A mutation in APP protects against Alzheimer's disease and age-related cognitive decline

机译：APP中的突变可预防阿尔茨海默氏病和与年​​龄有关的认知能力下降

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摘要

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APPin a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease p-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the p-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.%阿尔茨海默氏症的特征是，脑中有淀粉质斑块，后者是由于“淀粉样前体蛋白”(APP)的水解而形成的。通过对近2,000个基因组进行筛选，Kari Stefansson及其同事在APP基因上发现了一个编码突变，该突变可帮助防止患阿尔茨海默氏症和防止没有阿尔茨海默氏症症状的老年人认知能力下降。在试管中。该突变能使会产生淀粉质的肽的形成减少约40％。这种突变的强保护效应(突变位置在APP中的天冬氨酰蛋白酶贝塔点旁边)为以下假设提供了支持：减少APP的贝塔分解可防止息阿尔茨海默氏症。这些结果还提出一个可能性：阿尔茨海默氏症和老年人的认知能力下降在机制上是相关的。
机译：据估计，西方世界60岁以上人群的痴呆症患病率超过5％，其中约三分之二是由于阿尔茨海默氏病。 65岁以后，每5年特定年龄段的阿尔茨海默氏病患病率几乎翻倍，导致90岁以上的患病率高于25％（参考文献3）。在这里，为了搜索淀粉样β-前体蛋白（APP）基因中的低频变异体，该变异体对阿尔茨海默氏病的风险具有重大影响，我们在来自1,795个冰岛人的全基因组序列数据集中研究了APP中的编码变异体。我们在APP基因中发现了一个编码突变（A673T），该突变可预防老年痴呆症和无老年痴呆症的老年人的认知能力下降。这种取代与APP中的天冬氨酰蛋白酶p位相邻，导致体外产生淀粉样蛋白的肽形成减少了约40％。 A673T替代品对阿尔茨海默氏病的强大保护作用为以下假设提供了原理证明：减少APP的p裂解可预防该疾病。此外，由于A673T等位基因还可以预防无阿尔茨海默氏病的老年人的认知能力下降，因此两者可能通过相同或相似的机制介导。％阿尔茨海默氏症的特征是，脑中有淀粉质斑块，后通过对近2,000个基因组进行筛选，Kari Stefansson及其同事在APP基因上发现了一个编码突变，该突变可帮助防止患阿尔茨海默氏症和防止没有阿尔茨海默氏症症状的老年认知能力下降。在试管中。该突变能使会产生淀粉质的肽的形成减少约40％。这种突变的强保护效应（突变位置在APP中的天冬氨酰替代蛋白酶贝塔点旁边）为以下假设提供了支持：减少APP的贝塔分解可防止息阿尔茨海默氏症。这些结果还提出了一个可能：阿尔茨海默氏症和老年人的认知能力下降在机制上是相关的。

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  • 来源
    《Nature》 |2012年第7409期|p.96-99A2|共5页
  • 作者

    Thorlakur Jonsson; Jasvinder K. Atwal; Stacy Steinberg; Jon Snaedal; Palmi V. Jonsson; Sigurbjorn Bjornsson; Hreinn Stefansson; Patrick Sulem; Daniel Gudbjartsson; Janice Maloney; Kwame Hoyte$~2Amy Gustafson; Yichin Liu; Yanmei Lu; Tushar Bhangale; Robert R. Graham; Johanna Huttenlocher; Gyda Bjornsdottir; Ole A. Andreassen; Erik G. Joensson; Aarno Palotie; Timothy W. Behrens; Olafur T. Magnusson; Augustine Kong; Unnur Thorsteinsdottir; Ryan J. Watts; Kari Stefansson;

  • 作者单位

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland;

    Genentech, 1 DNA Way, South San Francisco, California 94080, USA;

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland;

    Landspitali University Hospital, Department of Geriatrics, 101 Reykjavik, Iceland;

    Landspitali University Hospital, Department of Geriatrics, 101 Reykjavik, Iceland,University of Iceland, Faculty of Medicine, 101 Reykjavik, Iceland;

    Landspitali University Hospital, Department of Geriatrics, 101 Reykjavik, Iceland;

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland;

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland;

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland;

    Genentech, 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, 1 DNA Way, South San Francisco, California 94080, USA;

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland,Department of Medical Genetics, Institute for Human Genetics, 72026 Tuebingen, Germany;

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland;

    Department of Psychiatry, Ulleval University Hospital and Institute of Psychiatry, University of Oslo, N-0407 Oslo, Norway;

    Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, SE-171 76 Stockholm, Sweden;

    Department of Medical Genetics, University of Helsinki, 00014 Helsinki, Finland;

    Genentech, 1 DNA Way, South San Francisco, California 94080, USA;

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland;

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland;

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland,University of Iceland, Faculty of Medicine, 101 Reykjavik, Iceland;

    Genentech, 1 DNA Way, South San Francisco, California 94080, USA;

    DeCODE genetics, Sturlugata 8,101 Reykjavik, Iceland,University of Iceland, Faculty of Medicine, 101 Reykjavik, Iceland;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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