Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes

Yang Hongyan; Wang Yanlin; Kar Satyabrata

摘要

Abstract > Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play an important role in the degeneration of neurons and development of Alzheimer's disease (AD). Current evidence indicates that high levels of cholesterol—which increase the risk of developing AD—can influence Aβ production in neurons. However, it remains unclear how altered level/subcellular distribution of cholesterol in astrocytes can influence APP metabolism. In this study, we evaluated the effects of cholesterol transport inhibitor U18666A—a class II amphiphile that triggers redistribution of cholesterol within the endosomal–lysosomal (EL) system—on APP levels and metabolism in rat primary cultured astrocytes. Our results revealed that U18666A increased the levels of the APP holoprotein and its cleaved products (α‐/β‐/η‐CTFs) in cultured astrocytes, without altering the total levels of cholesterol or cell viability. The cellular levels of Aβ <sub>1‐40</sub> were also found to be markedly increased, while secretory levels of Aβ <sub>1‐40</sub> were decreased in U18666A‐treated astrocytes. We further report a corresponding increase in the activity of the enzymes regulating APP processing, such as α‐secretase, β‐secretase, and γ‐secretase as a consequence of U18666A treatment. Additionally, APP‐cleaved products are partly accumulated in the lysosomes following cholesterol sequestration within EL system possibly due to decreased clearance. Interestingly, serum delipidation attenuated enhanced levels of APP and its cleaved products following U18666A treatment. Collectively, these results suggest that cholesterol sequestration within the EL system in astrocytes can influence APP metabolism and the accumulation of APP‐cleaved products including Aβ peptides, which can contribute to the development of </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><abstract xmlns =“http://www.wiley.com/namespaces/wiley”type =“main”> <title type =“main”>抽象</ title> >淀粉样蛋样β（aβ）肽产生淀粉样蛋白前体蛋白（APP）在神经元的退化和阿尔茨海默病（AD）的变性中起重要作用。目前的证据表明，高水平的胆固醇 - 这增加了发育广告的风险 - 可以影响神经元中的Aβ产生。然而，仍然尚不清楚星形胶质细胞中胆固醇的水平/亚细胞分布如何影响APP代谢。在这项研究中，我们评估了胆固醇转运抑制剂U18666A-A II类两亲型两种两种两种的影响，其触发胆固醇在大鼠原发性培养的星形胶质细胞中的应用水平和代谢内的胆固醇的再分布。我们的研究结果表明，U18666A增加了应用全蛋白酶和其切割产物（α-/β-/η-CTFS）在培养的星形胶质细胞中的水平，而不改变胆固醇或细胞活力的总水平。发现Aβ<sub> 1-40s </ sub>的细胞水平显着增加，而U18666A治疗的星形胶质细胞的Aβ<sub> 1-40s </ sub>的分泌水平降低。我们进一步报告了根据U18666A治疗的结果调节酶调节APP处理的酶的活性的相应增加，例如α-分泌酶，β-分泌酶和γ分泌酶。另外，在EL系统内的胆固醇封存之后，APP-Cleaved产品部分在EL系统中的胆固醇螯合后累积在溶酶体中，可能是由于间隙下降。有趣的是，在U18666A治疗后，血清Delipidation衰减了增强的应用水平及其切割产品。总的来说，这些结果表明，在星形胶质细胞中的EL系统内胆固醇封存可以影响应用新陈代谢和应用程序切割产品的积累，包括Aβ肽，这可能有助于开发 </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" >著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-23771/'>《Glia》</a> <b style="margin: 0 2px;">|</b><span>2017年第11期</span><b style="margin: 0 2px;">|</b><span>共16页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Yang Hongyan&option=202" target="_blank" rel="nofollow">Yang Hongyan;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Wang Yanlin&option=202" target="_blank" rel="nofollow">Wang Yanlin;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Kar Satyabrata&option=202" target="_blank" rel="nofollow">Kar Satyabrata;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Department of PsychiatryCentre for Prions and Protein Folding Diseases University of AlbertaEdmonton Alberta T6G 2M8 Canada;</p> <p>Department of PsychiatryCentre for Prions and Protein Folding Diseases University of AlbertaEdmonton Alberta T6G 2M8 Canada;</p> <p>Department of PsychiatryCentre for Prions and Protein Folding Diseases University of AlbertaEdmonton Alberta T6G 2M8 Canada;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li > <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span><a href="https://www.zhangqiaokeyan.com/clc/200.html" title="神经病学与精神病学">神经病学与精神病学;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Alzheimer's disease&option=203" rel="nofollow">Alzheimer's disease;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=APP processing&option=203" rel="nofollow">APP processing;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=β‐amyloid peptide&option=203" rel="nofollow">β‐amyloid peptide;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=endosomal–lysosomal system&option=203" rel="nofollow">endosomal–lysosomal system;</a> </p> <div class="translation"> 机译：阿尔茨海默病;应用处理;β-淀粉样肽;内体溶酶体系统; </div> </li> </ul> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" id="enpatent66">相似文献</h3> <div class="similaritytab clearfix"> <ul> <li class="active" >外文文献</li> <li >中文文献</li> <li >专利</li> </ul> </div> <div class="similarity_details"> <ul > <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/journal-foreign-detail/0704023429566.html">Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Yang Hongyan&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Yang Hongyan,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Wang Yanlin&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Wang Yanlin,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Kar Satyabrata&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Kar Satyabrata </a> <a href="/journal-foreign-23771/" target="_blank" rel="nofollow" class="tuijian_authcolor">Glia .</a> <span>2017</span><span>,第11期</span> </span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：胆固醇转运抑制剂U18666A对大鼠原发性星形胶质细胞应用代谢的影响</span> </p> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/journal-foreign-detail/070408021354.html">Cholesterol synthesis in the vertebrate retina: effects of U18666A on rat retinal structure, photoreceptor membrane assembly, and sterol metabolism and composition.</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Fliesler SJ&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Fliesler SJ,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Richards MJ&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Richards MJ,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Miller CY&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Miller CY,</a> <a href="/journal-foreign-26450/" target="_blank" rel="nofollow" class="tuijian_authcolor">Lipids .</a> <span>2000</span><span>,第3期</span> </span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：脊椎动物视网膜中的胆固醇合成：U18666A对大鼠视网膜结构，感光膜组装以及甾醇代谢和组成的影响。</span> </p> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/academic-journal-foreign_biochemistry_thesis/020418986926.html">Implication of apoE isoforms in cholesterol metabolism by primary rat hippocampal neurons and astrocytes</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Rapp A&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Rapp A,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Gmeiner B&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Gmeiner B,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Huttinger M&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Huttinger M </a> <a href="/journal-foreign-7722/" target="_blank" rel="nofollow" class="tuijian_authcolor">Biochimie .</a> <span>2006</span><span>,第5期</span> </span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：apoE亚型对原代大鼠海马神经元和星形胶质细胞胆固醇代谢的影响</span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/academic-conference-foreign_meeting-190565_thesis/020512898401.html">THE EFFECTS OF MACROMOLECULAR SUBSTRATES AND A METABOLIC INHIBITOR ON VOLATILE FATTY ACID METABOLISM IN THERMOPHILIC AEROBIC DIGESTION</a> <b>[C]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=A. 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href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=高慧&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 高慧</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=佟铁壁&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,佟铁壁</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=李春江&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,李春江</a> <span> <a href="/journal-cn-56678/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 临床军医杂志 </a> </span> <span> . 2018</span><span>,第5期</span> </span> </div> </li> <li> <div> <b>6. </b><a class="enjiyixqcontent" href="/academic-conference-cn_meeting-58647_thesis/020222538508.html">胆固醇酯转运蛋白变异体I le405al对血清高密度脂蛋白代谢的影响</a> <b>[C]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=陆付耳&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 陆付耳</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Heiko Wiebusch&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,Heiko Wiebusch</a> <span> <a href="/conference-cn-58647/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 中国科协第三届青年学术年会 </a> <span> <span> . 1998</span> </span> </div> </li> <li> <div> <b>7. </b><a class="enjiyixqcontent" href="/academic-degree-domestic_mphd_thesis/020312694290.html">可溶性环氧化物水解酶抑制剂对脂肪细胞介导胆固醇逆转运的影响</a> <b>[A] </b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=沈莉&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 沈莉</a> <span> . 2012</span> </span> </div> </li> </ul> <ul style="display: none;"> <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/patent-detail/061204428903.html">原代星形胶质细胞/原代中脑腹侧神经元共培养体系在星形胶质细胞与神经元间铁代谢研究中的应用</a> <b>[P]</b> . <span> 中国专利： CN110205294B </span> <span> . 2021.05.28</span> </div> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/patent-detail/061201167029.html">选择性的苄胺衍生物和其作为胆固醇酯转运蛋白抑制剂的应用</a> <b>[P]</b> . <span> 中国专利： CN101448397B </span> <span> . 2013.04.24</span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130441609097.html">COMPOSITION FOR REGULATING CHOLESTEROL METABOLISM IN BLOOD AND PREPARATION PROCESS THEREOF TO INHIBIT WEIGHT INCREASE AND REDUCE TOTAL CHOLESTEROL, IN PARTICULAR LOW DENSITY LIPO-PROTEIN</a> <b>[P]</b> . <span> 外国专利：  KR20040076452A </span> <span> . 2004-09-01</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：调节血液中胆固醇代谢的组合物及其制备过程，以抑制体重增加和减少特别是低密度脂蛋白的胆固醇总量 </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130457334696.html">USE OF DERIVATIVES OF DIOXABICICLO (3.3.0) OCTANO FOR THE PREPARATION OF A MEDICATION TO INHIBIT THE METABOLISM OF CHOLESTEROL.</a> <b>[P]</b> . <span> 外国专利：  ES2087252T3 </span> <span> . 1996-07-16</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：使用二恶英（3.3.0）辛酸衍生物制备药物以抑制胆固醇的代谢。 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130420144576.html">VERTEBRATE INTESTINAL PROTEIN WHICH ABSORBS CHOLESTEROL, AND THE USE OF THIS PROTEIN FOR IDENTIFYING INHIBITORS OF INTESTINAL CHOLESTEROL TRANSPORT</a> <b>[P]</b> . <span> 外国专利：  CA2420652C </span> <span> . 2013-04-02</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：吸收胆固醇的脊椎动物小肠蛋白，以及该蛋白在识别肠胆固醇运输抑制剂中的用途 </span> </p> </li> </ul> </div> </div> </div> <div class="theme cardcommon" style="overflow: auto;display:none"> <h3 class="all_title" id="enpatent55">相关主题</h3> 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