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Reversing EphB2 depletion rescues cognitive functions in Alzheimer model

机译：逆转EphB2耗竭可挽救阿尔茨海默病模型中的认知功能

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摘要

Amyloid-β oligomers may cause cognitive deficits in Alzheimer's disease by impairing neuronal NMDA-type glutamate receptors, whose function is regulated by the receptor tyrosine kinase EphB2. Here we show that amyloid-β oligomers bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer's disease and related models, we used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centres of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation in the dentate gyms, which are important for memory formation. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, depletion of EphB2 is critical in amyloid-β-induced neuronal dysfunction. Increasing EphB2 levels or function could be beneficial in Alzheimer's disease.
机译：淀粉样蛋白-β低聚物可能通过损害神经元NMDA型谷氨酸受体来引起阿尔茨海默氏病的认知缺陷，该受体的功能由受体酪氨酸激酶EphB2调节。在这里，我们显示淀粉样蛋白-β寡聚物与EphB2的纤连蛋白重复域结合并触发蛋白酶体中EphB2降解。为了确定EphB2耗竭在阿尔茨海默氏病和相关模型中的致病重要性，我们使用慢病毒构建体来减少或增加小鼠大脑记忆中心中EphB2的神经元表达。在非转基因小鼠中，由短发夹RNA介导的EphB2的敲低减少了NMDA受体电流并损害了齿状体育馆的长期增强能力，这对记忆形成很重要。人类淀粉样蛋白前体蛋白转基因小鼠的齿状回中EphB2表达的增加逆转了NMDA受体依赖性长期增强和记忆障碍的缺陷。因此，EphB2的耗竭在淀粉样β诱导的神经元功能障碍中至关重要。 EphB2水平或功能的增加可能对阿尔茨海默氏病有益。

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  • 来源
    《Nature》 |2011年第7328期|p.47-52|共6页
  • 作者

    Moustapha Cisse; Brian Halabisky; Julie Harris; Nino Devidze; Dena B. Dubai; Binggui Sun; Anna Orr; Gregor Lotz; Daniel H. Kim; Patricia Hamto; Kaitlyn Ho; Gui-Qiu Yu; Lennart Mucke;

  • 作者单位

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA,Department of Neurology, University of California, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA,Department of Neurology, University of California, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA,Department of Neurology, University of California, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA,Department of Neurology, University of California, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA,Department of Neurology, University of California, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA,Department of Neurology, University of California, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA,Department of Neurology, University of California, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA;

    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA,Department of Neurology, University of California, San Francisco, California 94158, 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);
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