Involvement of the Apoer2 and Lrp1 receptors in mediating the pathological effects of ApoE4 in vivo.
Involvement of the Apoer2 and Lrp1 receptors in mediating the pathological effects of ApoE4 in vivo.
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DOI：
10.2174/1567205010666131119232444
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发表时间：
2014
影响因子：
2.1
通讯作者：
Michaelson DM
中科院分区：
文献类型：
--
作者：
Gilat-Frenkel M;Boehm-Cagan A;Liraz O;Xian X;Herz J;Michaelson DM
本研究探讨了ApoE受体Lrp 1和Apoer 2在介导ApoE 4在表达人ApoE 3或ApoE 4等位基因的ApoE靶向替代小鼠中的病理效应中的可能作用。在这项研究中，我们发现，通过抑制Aβ降解酶脑啡肽酶激活淀粉样蛋白级联反应，导致4月龄ApoE 4小鼠CA 1海马神经元中ApoE受体Lrp 1上调，但在相应的ApoE 3或ApoE缺陷（KO）小鼠中则没有。这些结果与先前的发现一致，即淀粉样蛋白级联的激活诱导Aβ在ApoE 4小鼠的CA 1神经元中蓄积，但不在ApoE 3或ApoE-KO小鼠中蓄积。这表明apoE 4驱动的Lrp 1升高是通过功能获得机制介导的，并且可能在介导ApoE 4对Aβ的作用中起作用。相比之下，在脑啡肽酶抑制后未观察到相应Apoer 2受体水平的变化。ApoE受体的幼稚ApoE 4小鼠也受到差异和亚型特异性ApoE 4。然而，在这些条件下，作用是ApoE 4驱动的CA 1和CA 3锥体神经元中Apoer 2水平的降低，而Lrp 1水平不受影响。RT-PCR测量结果显示，未处理和脑啡肽抑制小鼠海马中Apoer 2和Lrp 1 mRNA的水平不受ApoE 4的影响，这表明ApoE 4对这些受体水平的影响是转录后的。总之，本研究表明，海马ApoE受体Lrp 1和Apoer 2在体内的水平受到ApoE 4特异性亚型的影响，并且受影响的受体类型是环境依赖性的。
This study investigated the possible role of the ApoE receptors Lrp1 and Apoer2 in mediating the pathological effects of ApoE4 in ApoE-targeted-replacement mice expressing either the human ApoE3 or ApoE4 allele. In this study we show that activation of the amyloid cascade by inhibition of the Aβ-degrading enzyme neprilysin results in up-regulation of the ApoE receptor Lrp1 in the CA1 hippocampal neurons of 4-month-old ApoE4 mice, but not in the corresponding ApoE3 or ApoE-deficient (KO) mice. These results are in accordance with the previous findings that activation of the amyloid cascade induces Aβ accumulation in the CA1 neurons of ApoE4 mice, but not in ApoE3 or ApoE-KO mice. This suggests that the apoE4-driven elevation of Lrp1 is mediated via a gain of function mechanism and may play a role in mediating the effects of ApoE4 on Aβ. In contrast, no changes were observed in the levels of the corresponding Apoer2 receptor following the neprilysin inhibition. The ApoE receptors of naive ApoE4 mice were also affected differentially and isoform specifically by ApoE4. However, under these conditions, the effect was an ApoE4-driven reduction in the levels of Apoer2 in CA1 and CA3 pyramidal neurons, whereas the levels of Lrp1 were not affected. RT-PCR measurements revealed that the levels of Apoer2 and Lrp1 mRNA in the hippocampus of naïve and neprilysin-inhibited mice were not affected by ApoE4, suggesting that the observed effects of ApoE4 on the levels of these receptors is post-transcriptional. In conclusion, this study shows that the levels of hippocampal ApoE receptors Lrp1 and Apoer2 in vivo are affected isoform specifically by ApoE4 and that the type of receptor affected is context dependent.
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DOI：
10.3233/jad-2010-101008
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Belinson H;Kariv-Inbal Z;Kayed R;Masliah E;Michaelson DM
通讯作者：
Michaelson DM
影响因子：
34.7
作者：
Bu, Guojun
通讯作者：
Bu, Guojun
影响因子：
5.3
作者：
Hartman, RE;Wozniak, DF;Holtzman, DM
通讯作者：
Holtzman, DM
影响因子：
5.3
作者：
Hayashi, Hideki;Campenot, Robert B.;Vance, Jean E.
通讯作者：
Vance, Jean E.
影响因子：
5.3
作者：
He, Xiangyuan;Cooley, Kathleen;Tang, Jordan
通讯作者：
Tang, Jordan