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Cited by 146Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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

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Liu, Chia-Chen, Wang, Na, Chen, Yuanxin, Inoue, Yasuteru, Shue, Francis, Ren, Yingxue, Wang, Minghui, Qiao, Wenhui +21 more·2023·Nature Immunology
DOI 10.1038/s41590-023-01640-9PMC PMC11980647
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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.

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  • APOE4 has been reported to impair TLR4 trafficking and downstream signaling in myeloid cells.

    “APOE4 has been reported to impair TLR4 trafficking and downstream signaling in myeloid cells (Vitek et al., 2009; Liu et al., 2023)”

    From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Liu et al., 2023

    The Results section on APOE isoform-dependent transcriptomic signatures reports that apoE4 fails to activate, or has the opposite effect on, several immune-response pathways in microglia. That supports impaired myeloid-cell responsiveness broadly, but the passages found do not address TLR4 trafficking or TLR4-specific downstream signaling (searched: TLR4 trafficking, TLR4, and toll-like receptor 4 signaling). (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Microglia and astrocytes have APOE genotype-dependent immune and inflammatory metabolic changes.

    “Additionally, microglia and astrocytes, which have been extensively studied in vivo, have APOE genotype dependent immune and inflammatory metabolic changes 22,25,26 .”

    From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [25]

    The Results sections on APOE isoform-dependent microglial signatures and human microglial lipid metabolism report genotype-dependent differences in immune responses and lipid accumulation. The Discussion mentions interactions with astrocytes but says that cell-type- and isoform-specific effects on glial function warrant further investigation; it does not establish the claimed changes in astrocytes. Page numbers were not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • APOE is involved in the regulation of DAMs and the microglial response to amyloid.

    “APOE is involved in the regulation of DAMs and the microglial response to amyloid [57, 64–66].”

    From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [66]

  • Recent data suggests a cell autonomous role of microglia-specific APOE4 expression in blocking the DAM response, compared to APOE3.

    “Recent data also suggests a cell autonomous role of microglia-specific APOE4 expression in blocking the DAM response, compared to APOE3 (Yin et al, 2023b; Liu et al, 2023).”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Liu et al, 2023

  • ApoE is a droplet-associated protein found on the lipid droplet surface.

    “ApoE is also droplet-associated protein found on the LD surface (Liu et al., 2023; Bersuker et al., 2018)”

    From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Liu et al., 2023

    The Results sections report that apoE4 expression increases lipid droplet accumulation in microglia, but they do not establish that apoE protein is associated with droplets or located on their surface. Searches for apoE localization at the lipid droplet surface found no passage addressing that point. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Liu, C.-C., Wang, N., Chen, Y., Inoue, Y., Shue, F., Ren, Y., Wang, M., Qiao, W., Ikezu, T. C., Li, Z., Zhao, J., Martens, Y., Doss, S. V., Rosenberg, C. L., Jeevaratnam, S., Jia, L., Raulin, A.-C., Qi, F., Zhu, Y., Alnobani, A., Knight, J., Chen, Y., Linares, C., Kurti, A., Fryer, J. D., Zhang, B., Wu, L.-J., Kim, B. Y. S., & Bu, G.
Affiliations
  • Biogen (United States) (US)
  • Mayo Clinic (US)
  • Mayo Clinic in Florida (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Hong Kong University of Science and Technology (HK)
Corresponding author
  • Liu, Chia-Chen
  • Bu, Guojun
ORCID
Venue
Nature Immunology
Publisher
Springer Science and Business Media LLC
Published
2023-10-19
Volume
24
Issue
11
Pages
1854-1866
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
DOI
10.1038/s41590-023-01640-9
PMC
PMC11980647
OpenAlex
W4387781913
Cited by
146
References
33
Citations by year
2026: 56 · 2025: 43 · 2024: 43 · 2023: 4
FWCI
14.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (AG027924, AG069701, AG062110)
  • Cure Alzheimer’s Fund
  • BrightFocus Foundation (A20201542S)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
apolipoprotein E, APOE ε4, APOE3, microglia, Alzheimer's disease, amyloid plaques, lipid droplets, antigen presentation, interferon pathway, complement pathway, lysosomal pathway, cognitive function, brain homeostasis, galectin-3, induced pluripotent stem cell-derived microglia
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Homeostasis, Humans, Mice, Transgenic, Microglia, Mice, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid

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