Cell Metabolism:袁增强/孙露洋合作揭示阿尔茨海默病新机制

2022-03-19 “ 生物世界”公众号 “ 生物世界”公众号

阿尔茨海默病(AD),俗称老年痴呆,是最主要的神经退行性疾病,其发病率高,危害大,随着全球人口老龄化的日益加剧,AD患者数量不断上升。

阿尔茨海默病(AD),俗称老年痴呆,是最主要的神经退行性疾病,其发病率高,危害大,随着全球人口老龄化的日益加剧,AD患者数量不断上升,但到目前为止,其发病机制尚不清楚,临床上缺乏对AD有效的治疗药物或手段。

小胶质细胞是中枢神经系统中的固有免疫细胞,参与神经元突触的修剪、髓鞘的形成、细胞碎片及错误折叠蛋白的清除等一系列生物过程,与大脑发育、脑生理功能维持以及各种脑疾病的发生发展密切相关。大量的研究表明,小胶质细胞及其介导的神经炎症在AD的发生发展过程中发挥至关重要的作用,但具体的分子机制仍未阐明。

2022年3月17日,军事医学研究院袁增强课题组联合北京大学孙露洋课题组在 Cell Metabolism 期刊发表了题为:Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease 的研究论文。

该研究揭示了小胶质细胞代谢紊乱形成的“糖酵解-组蛋白乳酸化-PKM2”恶性循环能够导致小胶质细胞稳态失衡和神经炎症的发生,进而促进阿尔茨海默病发生发展的表观遗传调控机制。

在这项研究中,合作研究团队从AD临床脑标本和模型小鼠脑组织出发,发现在AD背景下小胶质细胞糖酵解过度激活,导致乳酸在细胞内累积,进而导致组蛋白乳酸化修饰异常升高,而升高的组蛋白乳酸化修饰可以促进糖酵解相关基因的转录激活,形成的“糖酵解-组蛋白乳酸化-PKM2”正反馈调控环路。

该环路恶化了小胶质细胞糖代谢紊乱,导致小胶质细胞稳态失衡及神经炎症的发生,进而促进AD的发生发展。通过靶向抑制PKM2阻断该“糖酵解-组蛋白乳酸化-PKM2”恶性循环,可以恢复小胶质细胞的代谢与功能稳态,减轻神经炎症反应,进而缓解AD的病理进程。

该研究揭示了AD发生发展中小胶质细胞糖代谢重塑的表观遗传调控机制,阐明代谢紊乱是神经炎症和AD发生发展的驱动事件,为AD的早期干预提供了新视角和新靶点。

军事医学研究院袁增强教授和北京大学孙露洋教授为该工作的共同通讯作者,军事医学研究院博士后潘瑞远博士和北京大学博士后何林博士为共同第一作者。

原始出处:

Rui-Yuan Pan, et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metabolism, 2022.

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    2022-04-03 维他命
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    2022-12-13 一闲
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time=2022-03-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577287, encodeId=9ecf15e728713, content=<a href='/topic/show?id=d86d1159e36' target=_blank style='color:#2F92EE;'>#Metabolism#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11597, encryptionId=d86d1159e36, topicName=Metabolism)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1a6516392333, createdName=1249859em43(暂无昵称), createdTime=Mon Mar 21 05:36:30 CST 2022, time=2022-03-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1598164, encodeId=4a40159816491, content=<a href='/topic/show?id=6c6f1e62c5' target=_blank style='color:#2F92EE;'>#ABO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1762, encryptionId=6c6f1e62c5, topicName=ABO)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b6c918580135, createdName=闆锋旦, createdTime=Mon Mar 21 05:36:30 CST 2022, time=2022-03-21, status=1, ipAttribution=)]
  5. [GetPortalCommentsPageByObjectIdResponse(id=1962721, encodeId=d7bb1962e21ad, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Sun Apr 03 21:36:30 CST 2022, time=2022-04-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1818197, encodeId=fb89181819eaf, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Sat May 21 23:36:30 CST 2022, time=2022-05-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1896993, encodeId=57d71896993de, content=<a href='/topic/show?id=4a391158248' target=_blank style='color:#2F92EE;'>#MET#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11582, encryptionId=4a391158248, topicName=MET)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=18fc139, createdName=一闲, createdTime=Tue Dec 13 11:36:30 CST 2022, time=2022-12-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1872396, encodeId=680e18e2396aa, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, 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content=<a href='/topic/show?id=d56611584ec' target=_blank style='color:#2F92EE;'>#Meta#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11584, encryptionId=d56611584ec, topicName=Meta)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d8f4110, createdName=guojianrong, createdTime=Fri Nov 11 23:36:30 CST 2022, time=2022-11-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470545, encodeId=8f6314e0545f1, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Mon Mar 21 05:36:30 CST 2022, time=2022-03-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577287, encodeId=9ecf15e728713, content=<a href='/topic/show?id=d86d1159e36' target=_blank style='color:#2F92EE;'>#Metabolism#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11597, encryptionId=d86d1159e36, topicName=Metabolism)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1a6516392333, createdName=1249859em43(暂无昵称), createdTime=Mon Mar 21 05:36:30 CST 2022, time=2022-03-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1598164, encodeId=4a40159816491, content=<a href='/topic/show?id=6c6f1e62c5' target=_blank style='color:#2F92EE;'>#ABO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1762, encryptionId=6c6f1e62c5, topicName=ABO)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b6c918580135, createdName=闆锋旦, createdTime=Mon Mar 21 05:36:30 CST 2022, time=2022-03-21, status=1, ipAttribution=)]
  6. [GetPortalCommentsPageByObjectIdResponse(id=1962721, encodeId=d7bb1962e21ad, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Sun Apr 03 21:36:30 CST 2022, time=2022-04-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1818197, encodeId=fb89181819eaf, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Sat May 21 23:36:30 CST 2022, time=2022-05-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1896993, encodeId=57d71896993de, content=<a href='/topic/show?id=4a391158248' target=_blank style='color:#2F92EE;'>#MET#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11582, encryptionId=4a391158248, topicName=MET)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=18fc139, createdName=一闲, createdTime=Tue Dec 13 11:36:30 CST 2022, time=2022-12-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1872396, encodeId=680e18e2396aa, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Thu Apr 07 04:36:30 CST 2022, time=2022-04-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817174, encodeId=c007181e174d3, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Fri Nov 11 20:36:30 CST 2022, time=2022-11-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1888420, encodeId=65e0188842057, content=<a href='/topic/show?id=d56611584ec' target=_blank style='color:#2F92EE;'>#Meta#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11584, encryptionId=d56611584ec, topicName=Meta)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d8f4110, createdName=guojianrong, createdTime=Fri Nov 11 23:36:30 CST 2022, time=2022-11-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470545, encodeId=8f6314e0545f1, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Mon Mar 21 05:36:30 CST 2022, time=2022-03-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577287, encodeId=9ecf15e728713, content=<a href='/topic/show?id=d86d1159e36' target=_blank style='color:#2F92EE;'>#Metabolism#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11597, encryptionId=d86d1159e36, topicName=Metabolism)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1a6516392333, createdName=1249859em43(暂无昵称), createdTime=Mon Mar 21 05:36:30 CST 2022, time=2022-03-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1598164, encodeId=4a40159816491, content=<a href='/topic/show?id=6c6f1e62c5' target=_blank style='color:#2F92EE;'>#ABO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1762, encryptionId=6c6f1e62c5, topicName=ABO)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b6c918580135, createdName=闆锋旦, createdTime=Mon Mar 21 05:36:30 CST 2022, time=2022-03-21, status=1, ipAttribution=)]
    2022-11-11 guojianrong
  7. [GetPortalCommentsPageByObjectIdResponse(id=1962721, encodeId=d7bb1962e21ad, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Sun Apr 03 21:36:30 CST 2022, time=2022-04-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1818197, encodeId=fb89181819eaf, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, 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content=<a href='/topic/show?id=d56611584ec' target=_blank style='color:#2F92EE;'>#Meta#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11584, encryptionId=d56611584ec, topicName=Meta)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d8f4110, createdName=guojianrong, createdTime=Fri Nov 11 23:36:30 CST 2022, time=2022-11-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470545, encodeId=8f6314e0545f1, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Mon Mar 21 05:36:30 CST 2022, 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  8. 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    2022-03-21 闆锋旦

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