香港科技大学卜国军研究组发现，载脂蛋白E (APOE)在脑稳态和阿尔茨海默病(AD)中限制小胶质细胞反应中的细胞自主作用。2023年10月19日出版的《自然—免疫学》杂志发表了这项成果。

通过在小胶质细胞和中枢神经系统相关巨噬细胞(CAMs)中表达apoE亚型的条件小鼠模型，他们证明了apoE3介导的小胶质细胞激活和功能的细胞自主效应，而apoE4会否定这些效应。apoE3在小胶质细胞/CAMs中的表达可以改善认知功能，增加淀粉样斑块周围的小胶质细胞，减少淀粉样蛋白病理和相关毒性，而apoE4的表达通过损害脂质代谢而损害或对这些结果没有影响。单细胞转录组分析显示apoE3表达后抗原呈递和干扰素通路增加。相反，apoE4表达下调补体和溶酶体途径，促进应激相关反应。

此外，在小鼠内源性apoE存在的情况下，小胶质细胞apoE4加剧了淀粉样蛋白病理。最后，他们观察到淀粉样斑块周围Lgals3阳性反应的小胶质细胞减少，APOE4人脑和诱导多能干细胞来源的小胶质细胞中脂滴积累增加。他们的研究结果确定了小胶质细胞/ CAM表达的apoE在脑功能和淀粉样蛋白病理发展中的关键同工型依赖性作用，为apoE4如何大大增加AD风险提供了新的见解。

据了解，小胶质细胞参与AD病理已成为一个决定风险的致病事件。虽然APOE已知可以改变AD的风险，但尚不清楚小胶质载脂蛋白E如何影响大脑认知和AD病理。

附：英文原文

Title: Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer’s disease

Author: Liu, Chia-Chen, Wang, Na, Chen, Yuanxin, Inoue, Yasuteru, Shue, Francis, Ren, Yingxue, Wang, Minghui, Qiao, Wenhui, Ikezu, Tadafumi C., Li, Zonghua, Zhao, Jing, Martens, Yuka, Doss, Sydney V., Rosenberg, Cassandra L., Jeevaratnam, Suren, Jia, Lin, Raulin, Ana-Caroline, Qi, Fangfang, Zhu, Yiyang, Alnobani, Alla, Knight, Joshua, Chen, Yixing, Linares, Cynthia, Kurti, Aishe, Fryer, John D., Zhang, Bin, Wu, Long-Jun, Kim, Betty Y. S., Bu, Guojun

Issue&Volume: 2023-10-19

Abstract: Microglial involvement in Alzheimer’s disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.

DOI: 10.1038/s41590-023-01640-9

Source: https://www.nature.com/articles/s41590-023-01640-9