• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >AP0E4 leads to blood-brain barrier dysfunction predicting cognitive decline
【24h】

AP0E4 leads to blood-brain barrier dysfunction predicting cognitive decline

机译：AP0E4导致血脑屏障功能障碍，预示认知能力下降

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Breakdown of the blood-brain barrier in individuals carrying the epsilon 4 allele of the APOE gene, but not the epsilon 3 allele, increases with and predicts cognitive impairment and is independent of amyloid beta or tau pathology.Vascular contributions to dementia and Alzheimer's disease are increasingly recognized(1-6). Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction(7), including the early clinical stages of Alzheimer's disease(5,8-10). The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease(11-14), leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes(15-19), which maintain BBB integrity(20-22). It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the epsilon 3/epsilon 4 or epsilon 4/epsilon 4 alleles) are distinguished from those without APOE4 (epsilon 3/epsilon 3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-beta or tau pathology measured in cerebrospinal fluid or by positron emission tomography(23). High baseline levels of the BBB pericyte injury biomarker soluble PDGFR beta(7,8) in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-beta and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway(19) in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.
机译：携带APOE基因的epsilon 4等位基因但不包含epsilon 3等位基因的人血脑屏障的破坏随着认知障碍的增加而增加，并与淀粉样β或tau病理无关，与血管性痴呆和阿尔茨海默氏病有关越来越被认可（1-6）。最近的研究表明，血脑屏障（BBB）的破坏是人类认知功能障碍的早期生物标志物（7），包括阿尔茨海默氏病的早期临床阶段（5,8-10）。载脂蛋白E（APOE4）的E4变体是阿尔茨海默氏病的主要易感基因（11-14），导致BBB加速分解和脑毛细血管周细胞变性（15-19），从而维持BBB完整性（20-22） ）。但是，尚不清楚APOE4的脑血管效应是否会导致认知障碍。在这里，我们显示携带APOE4（具有epsilon 3 / epsilon 4或epsilon 4 / epsilon 4等位基因）的个体与没有APOE4（epsilon 3 / epsilon 3等位基因）的个体之间的区别在于海马和颞颞叶BBB的分解。这一发现在没有认知障碍的APOE4携带者中很明显，而在那些有认知障碍的携带者中更为严重，但与脑脊液或正电子发射断层扫描所测量的淀粉样β或tau病理无关（23）。脑脊液中BBB周细胞损伤生物标志物可溶性PDGFR beta（7,8）的高基线水平预测了APOE4携带者而非非携带者的未来认知能力下降，即使在控制了淀粉样β和tau状况后，也与之相关增加脑脊液中降解BBB的亲环蛋白A-基质金属蛋白酶9途径的活性（19）。我们的发现表明，BBB的分解独立于阿尔茨海默氏病病理而助长了与APOE4相关的认知功能下降，并且可能是APOE4携带者的治疗靶标。

著录项

  • 来源
    《Nature》 |2020年第7806期|71-76|共6页
  • 作者

  • 作者单位

    Univ Southern Calif Keck Sch Med Zilkha Neurogenet Inst Dept Physiol & Neurosci Los Angeles CA 90007 USA;

    Univ Southern Calif Keck Sch Med Zilkha Neurogenet Inst Dept Physiol & Neurosci Los Angeles CA 90007 USA|Univ Southern Calif Keck Sch Med Alzheimers Dis Res Ctr Los Angeles CA 90007 USA|Univ Calif Irvine Dept Psychol Sci Irvine CA USA|Univ Calif Irvine Inst Memory Disorders & Neurol Impairments Irvine CA USA;

    Univ Southern Calif Keck Sch Med Alzheimers Dis Res Ctr Los Angeles CA 90007 USA|Univ Southern Calif Keck Sch Med Dept Neurol Los Angeles CA 90007 USA;

    Huntington Med Res Inst Pasadena CA USA;

    Washington Univ Sch Med Dept Radiol St Louis MO 63110 USA|Washington Univ Sch Med Hope Ctr Neurodegenerat Disorders St Louis MO USA;

    Washington Univ Sch Med Hope Ctr Neurodegenerat Disorders St Louis MO USA|Washington Univ Sch Med Dept Neurol St Louis MO 63110 USA|Washington Univ Sch Med Knight Alzheimers Dis Res Ctr St Louis MO USA;

    Univ Southern Calif Keck Sch Med Alzheimers Dis Res Ctr Los Angeles CA 90007 USA|Univ Southern Calif Keck Sch Med Dept Neurol Los Angeles CA 90007 USA|Univ Southern Calif Dept Psychiat & Behav Sci Los Angeles CA 90007 USA;

    Washington Univ Sch Med Dept Neurol St Louis MO 63110 USA|Washington Univ Sch Med Knight Alzheimers Dis Res Ctr St Louis MO USA;

    Banner Alzheimer Inst Phoenix AZ USA;

    Mayo Clin Dept Neurol Scottsdale AZ USA;

    Icahn Sch Med Mt Sinai Dept Neurosci New York NY 10029 USA|Icahn Sch Med Mt Sinai Friedman Brain Inst New York NY 10029 USA|Icahn Sch Med Mt Sinai Ronald M Loeb Ctr Alzheimers Dis New York NY 10029 USA;

    Univ Southern Calif Keck Sch Med Alzheimers Dis Res Ctr Los Angeles CA 90007 USA|Univ Southern Calif Keck Sch Med USC Stevens Neuroimaging & Informat Inst Lab Neuroimaging Los Angeles CA 90007 USA;

    Univ Southern Calif Keck Sch Med Dept Radiol Mol Imaging Ctr Los Angeles CA 90007 USA;

    Univ Southern Calif Keck Sch Med Alzheimers Dis Res Ctr Los Angeles CA 90007 USA|Univ Southern Calif Keck Sch Med Dept Neurol Surg Los Angeles CA 90007 USA|Monash Univ Alfred Hlth Dept Neurosci & Radiol Melbourne Vic Australia;

    Univ Southern Calif Keck Sch Med Zilkha Neurogenet Inst Dept Physiol & Neurosci Los Angeles CA 90007 USA|Univ Southern Calif Keck Sch Med Alzheimers Dis Res Ctr Los Angeles CA 90007 USA;

  • 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);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号