Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits.
Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits.
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DOI：
10.1038/s43587-023-00368-3
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发表时间：
2023-03
期刊：
影响因子：
--
通讯作者：
Huang, Yadong
中科院分区：
文献类型：
--
作者：
Koutsodendris, Nicole;Blumenfeld, Jessica;Agrawal, Ayushi;Traglia, Michela;Grone, Brian;Zilberter, Misha;Yip, Oscar;Rao, Antara;Nelson, Maxine R.;Hao, Yanxia;Thomas, Reuben;Yoon, Seo Yeon;Arriola, Patrick;Huang, Yadong
载脂蛋白 E4 (APOE4) 是已知最强的迟发性阿尔茨海默病 (AD) 遗传风险因素。应激或损伤条件会诱导神经元内 APOE 表达，但神经元 APOE4 在 AD 发病机制中的作用仍不清楚。在这里，我们报告了表达 APOE4 的 tau 蛋白病小鼠模型中神经元 APOE4 对 AD 相关病理的影响。从神经元中选择性基因去除 APOE4 可显着减少 tau 病理、神经胶质增生、神经退行性变、神经元过度兴奋和髓磷脂缺陷。单核 RNA 测序显示，神经元 APOE4 的去除极大地减少了与神经退行性疾病相关的神经元、少突胶质细胞、星形胶质细胞和小胶质细胞亚群，这些亚群的积累与 tau 病理学、神经退行性变和髓磷脂缺陷的严重程度相关。因此，神经元 APOE4 在促进主要 AD 病理的发展中发挥着核心作用，其去除可以减轻 APOE4 驱动的 tau 蛋白病模型中发生的进行性细胞和组织改变。 APOE4是由神经元在应激下产生的，但神经元APOE4在阿尔茨海默病发病机制中的作用仍不清楚。作者在此报告称，选择性去除 tau 蛋白病小鼠中的神经元 APOE4 可减轻许多与阿尔茨海默氏病相关的突出病理。
Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy. APOE4 is produced by neurons under stress, but the role of neuronal APOE4 in Alzheimer’s disease pathogenesis is still unclear. Here the authors report that selective removal of neuronal APOE4 in tauopathy mice mitigates many prominent Alzheimer’s disease-related pathologies.
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影响因子：
25
作者：
Habib, Naomi;McCabe, Cristin;Medina, Sedi;Varshavsky, Miriam;Kitsberg, Daniel;Dvir-Szternfeld, Raz;Green, Gilad;Dionne, Danielle;Nguyen, Lan;Marshall, Jamie L.;Chen, Fei;Zhang, Feng;Kaplan, Tommy;Regev, Aviv;Schwartz, Michal
通讯作者：
Schwartz, Michal
影响因子：
14.9
作者：
Howe KL;Achuthan P;Allen J;Allen J;Alvarez-Jarreta J;Amode MR;Armean IM;Azov AG;Bennett R;Bhai J;Billis K;Boddu S;Charkhchi M;Cummins C;Da Rin Fioretto L;Davidson C;Dodiya K;El Houdaigui B;Fatima R;Gall A;Garcia Giron C;Grego T;Guijarro-Clarke C;Haggerty L;Hemrom A;Hourlier T;Izuogu OG;Juettemann T;Kaikala V;Kay M;Lavidas I;Le T;Lemos D;Gonzalez Martinez J;Marugán JC;Maurel T;McMahon AC;Mohanan S;Moore B;Muffato M;Oheh DN;Paraschas D;Parker A;Parton A;Prosovetskaia I;Sakthivel MP;Salam AIA;Schmitt BM;Schuilenburg H;Sheppard D;Steed E;Szpak M;Szuba M;Taylor K;Thormann A;Threadgold G;Walts B;Winterbottom A;Chakiachvili M;Chaubal A;De Silva N;Flint B;Frankish A;Hunt SE;IIsley GR;Langridge N;Loveland JE;Martin FJ;Mudge JM;Morales J;Perry E;Ruffier M;Tate J;Thybert D;Trevanion SJ;Cunningham F;Yates AD;Zerbino DR;Flicek P
通讯作者：
Flicek P
影响因子：
4.3
作者：
DeVos SL;Corjuc BT;Oakley DH;Nobuhara CK;Bannon RN;Chase A;Commins C;Gonzalez JA;Dooley PM;Frosch MP;Hyman BT
通讯作者：
Hyman BT
来自阿尔茨海默氏症大脑的独特病理tau构象体传播了非转基因小鼠的tau病理。
DOI：
10.1084/jem.20160833
发表时间：
2016-11-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guo JL;Narasimhan S;Changolkar L;He Z;Stieber A;Zhang B;Gathagan RJ;Iba M;McBride JD;Trojanowski JQ;Lee VM
通讯作者：
Lee VM
DOI：
10.1523/jneurosci.0033-12.2012
发表时间：
2012-04-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bien-Ly N;Gillespie AK;Walker D;Yoon SY;Huang Y
通讯作者：
Huang Y