美国加州大学旧金山分校Yadong Huang课题组发现，小胶质细胞清除可减少一种嵌合型阿尔茨海默病模型中人类神经元APOE4相关的病理变化。相关论文于2024年11月4日在线发表于国际学术期刊《细胞—干细胞》。

研究人员表示，尽管有充分证据支持载脂蛋白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明确。

为了研究这一影响，研究人员在一种嵌合模型中进行了小胶质细胞去除实验，模型中包括诱导多能干细胞（iPSC）衍生的人类神经元，移植于小鼠海马。具体来说，研究人员将同源APOE4、同源APOE3和APOE基因敲除（APOE-KO）iPSC衍生的人类神经元移植到人类APOE3或APOE4敲入小鼠的海马中，然后在一半的嵌合小鼠中去除小胶质细胞。

研究人员发现，神经元APOE和小胶质细胞的存在对Aβ和tau病理的形成非常重要，且这种作用依赖于APOE亚型（APOE4 > APOE3）。单细胞RNA测序分析识别出两种促炎性小胶质细胞亚型，这些亚型在移植有APOE4神经元的嵌合小鼠中，MHC-II基因表达显著升高。

这些发现突显了神经元APOE，尤其是APOE4，与小胶质细胞在AD发病机制中的协同作用。

附：英文原文

Title: Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer’s disease model

Author: Antara Rao, Nuo Chen, Min Joo Kim, Jessica Blumenfeld, Oscar Yip, Zherui Liang, David Shostak, Yanxia Hao, Maxine R. Nelson, Nicole Koutsodendris, Brian Grone, Leo Ding, Seo Yeon Yoon, Patrick Arriola, Misha Zilberter, Yadong Huang

Issue&Volume: 2024-11-04

Abstract: 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.

DOI: 10.1016/j.stem.2024.10.005

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00367-9