APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer's disease.
APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer's disease.
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APOE2在基于ISEGONIC HIPSC的阿尔茨海默氏病模型中减轻与疾病相关的表型。
DOI：
10.1038/s41380-021-01076-3
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发表时间：
2021-10
影响因子：
11
通讯作者：
Brafman DA
中科院分区：
文献类型：
--
作者：
Brookhouser N;Raman S;Frisch C;Srinivasan G;Brafman DA
全基因组关联研究已证实载脂蛋白E基因(APOE)的多态性是阿尔茨海默病(AD)最显著的危险因素。与APOE3变异纯合子个体相比，APOE4变异个体患AD的风险显著增加。另一方面，纵向研究表明，APOE2变异体的存在将患阿尔茨海默病的风险降低了40%。虽然已经有重要的研究确定了APOE4的风险诱导作用，但APOE2影响AD发生和进展的潜在机制尚未被广泛探索。在这项研究中，我们利用一个基于等基因人类诱导多能干细胞(HIPSC)的系统来证明，在HIPSC来源的神经培养中，APOE3到APOE2的转换大大减少了淀粉样β蛋白(Aβ)多肽的产生。从机制上讲，对来自这些神经培养物的纯神经元和星形胶质细胞群体的分析表明，APOE2的缓解作用是由细胞自主和非自主效应介导的。特别是，我们证明了Aβ的减少可能是由与淀粉样前体蛋白(APP)的非淀粉样变性处理相关的机制驱动的，这表明APOE2变体的保护功能获得了增强。总之，这项研究提供了与APOE2等位基因相关的风险调整效应的见解，并建立了一个平台来探索APOE2增强对AD的神经保护的机制。
Genome-wide association studies (GWAS) have identified polymorphism in the Apolipoprotein E gene (APOE) to be the most prominent risk factor for Alzheimer’s disease (AD). Compared to individuals homozygous for the APOE3 variant, individuals with the APOE4 variant have a significantly elevated risk of AD. On the other hand, longitudinal studies have shown that the presence of the APOE2 variant reduces the lifetime risk of developing AD by 40 percent. While there has been significant research that has identified the risk-inducing effects of APOE4, the underlying mechanisms by which APOE2 influences AD onset and progression have not been extensively explored. In this study, we utilize an isogenic human induced pluripotent stem cell (hiPSC)-based system to demonstrate that conversion of APOE3 to APOE2 greatly reduced the production of amyloid-beta (Aβ) peptides in hiPSC-derived neural cultures. Mechanistically, analysis of pure populations of neurons and astrocytes derived from these neural cultures revealed that mitigating effects of APOE2 are mediated by cell autonomous and non-autonomous effects. In particular, we demonstrated the reduction in Aβ is potentially driven by a mechanism related to non-amyloidogenic processing of amyloid precursor protein (APP), suggesting a gain of the protective function of the APOE2 variant. Together, this study provides insights into the risk-modifying effects associated with the APOE2 allele and establishes a platform to probe the mechanisms by which APOE2 enhances neuroprotection against AD.
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影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
影响因子：
2.5
作者：
Hjelm BE;Rosenberg JB;Szelinger S;Sue LI;Beach TG;Huentelman MJ;Craig DW
通讯作者：
Craig DW
影响因子：
3.5
作者：
Chow, Vivian W.;Mattson, Mark P.;Wong, Philip C.;Gleichmann, Marc
通讯作者：
Gleichmann, Marc
影响因子：
9.9
作者：
Berlau DJ;Corrada MM;Head E;Kawas CH
通讯作者：
Kawas CH
影响因子：
2.9
作者：
Holmberg, KH;Patterson, PH
通讯作者：
Patterson, PH