Journal Article

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

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

2023

Overview

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. Liu and colleagues find differential effects of microglial apoE isoforms on brain function and microglial responses. ApoE3 enhances microglial responses, promoting brain function and reducing amyloid deposition and associated neurotoxicity, while the Alzheimer’s disease-associated apoE4 results in lipid droplet accumulation and impaired microglial responses, which are critical for limiting the development of amyloid pathology.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250 / 631/80 / Alzheimer Disease - genetics / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid / Animal models / Animals / Antigen presentation / Apolipoprotein E / Apolipoprotein E3 - genetics / Apolipoprotein E3 - metabolism / Apolipoprotein E4 / Apolipoprotein E4 - genetics / Apolipoprotein E4 - metabolism / Apolipoproteins E - genetics / Apolipoproteins E - metabolism / Biomedical and Life Sciences / Biomedicine / Brain / Brain - metabolism / Central nervous system / Cognitive ability / Homeostasis / Humans / Immunology / Infectious Diseases / Isoforms / Lipid metabolism / Lipids / Macrophages / Mice / Mice, Transgenic / Microglia / Microglia - metabolism / Neurodegenerative diseases / Neurotoxicity / Pathology / Plaque, Amyloid - metabolism / Plaque, Amyloid - pathology / Pluripotency / Stem cells / Transcriptomics