Rao Antara, Chen Nuo, Kim Min Joo, Blumenfeld Jessica, Yip Oscar, Liang Zherui, Shostak David, Hao Yanxia, Nelson Maxine R, Koutsodendris Nicole, Grone Brian, Ding Leo, Yoon Seo Yeon, Arriola Patrick, Zilberter Misha, Huang Yadong
Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA.
Cell Stem Cell. 2025 Jan 2;32(1):86-104.e7. doi: 10.1016/j.stem.2024.10.005. Epub 2024 Nov 4.
Despite strong evidence supporting the important roles of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-related AD pathogenesis remain elusive. To examine such effects, we utilized microglial depletion in a chimeric model with induced pluripotent stem cell (iPSC)-derived human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) iPSC-derived human neurons into the hippocampus of human APOE3 or APOE4 knockin mice and then depleted microglia in half of the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA sequencing analysis identified two pro-inflammatory microglial subtypes with elevated MHC-II gene expression enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.
尽管有强有力的证据支持载脂蛋白E4（APOE4）和小胶质细胞在阿尔茨海默病（AD）发病机制中的重要作用，但小胶质细胞对神经元APOE4相关AD发病机制的影响仍不清楚。为了研究这些影响，我们在一个嵌合模型中利用小胶质细胞耗竭，该模型将诱导多能干细胞（iPSC）衍生的人类神经元植入小鼠海马体。具体而言，我们将纯合APOE4、同基因APOE3和APOE基因敲除（APOE-KO）的iPSC衍生的人类神经元移植到人类APOE3或APOE4基因敲入小鼠的海马体中，然后在一半的嵌合小鼠中耗竭小胶质细胞。我们发现，神经元APOE和小胶质细胞的存在对于以APOE异构体依赖的方式（APOE4 > APOE3）形成Aβ和tau病理都很重要。单细胞RNA测序分析确定了两种促炎性小胶质细胞亚型，其MHC-II基因表达升高，在移植了人类APOE4神经元的嵌合小鼠中富集。这些发现突出了神经元APOE，尤其是APOE4和小胶质细胞在AD发病机制中的协同作用。
