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Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease
Chia-Chen Liu1,2, Na Wang3,4, Yuanxin Chen3
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. liu.chiachenjen@gmail.com.
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.
Insights
Apolipoprotein E4 (APOE4) in microglia worsens Alzheimer's disease (AD) pathology and cognitive decline. Microglial APOE3, however, improves brain function and reduces amyloid plaques, highlighting isoform-specific effects in AD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglial cells play a crucial role in Alzheimer's disease (AD) pathogenesis.
- Apolipoprotein E (APOE) is a known risk factor for AD, but its specific role within microglia is not fully understood.
- Understanding microglial APOE function is key to deciphering AD risk associated with APOE isoforms.
Purpose of the Study:
- To investigate the cell-autonomous effects of apolipoprotein E (APOE) isoforms expressed in microglia and central nervous system-associated macrophages (CAMs) on brain cognition and Alzheimer's disease (AD) pathology.
- To elucidate the molecular mechanisms underlying APOE isoform-dependent microglial function in the context of AD.
- To determine how microglial APOE4 exacerbates AD pathology compared to APOE3.
Main Methods:
- Utilized conditional mouse models expressing specific APOE isoforms (APOE3, APOE4) in microglia and CAMs.
- Assessed cognitive function, amyloid plaque load, and associated toxicity in the mouse models.
- Performed single-cell transcriptomic profiling to analyze microglial responses.
- Examined lipid metabolism and microglial markers in human brain samples and iPSC-derived microglia.
Main Results:
- Microglial APOE3 expression improved cognitive function, increased microglia around amyloid plaques, and reduced amyloid pathology and toxicity.
- Microglial APOE4 expression impaired lipid metabolism, leading to compromised or no beneficial effects on cognition and pathology.
- Single-cell RNA sequencing revealed APOE3 upregulated antigen presentation and interferon pathways, while APOE4 downregulated complement/lysosomal pathways and increased stress responses.
- Microglial APOE4 exacerbated amyloid pathology in the presence of endogenous mouse APOE.
- Human APOE4 brains and iPSC-derived microglia showed reduced responsive microglia and increased lipid droplet accumulation.
Conclusions:
- Microglia-specific APOE isoforms exert critical, cell-autonomous effects on brain function and AD pathology.
- APOE3 in microglia/CAMs is neuroprotective, whereas APOE4 is detrimental, largely due to impaired lipid metabolism and altered immune responses.
- These findings provide novel insights into how APOE4 significantly elevates AD risk and suggest potential therapeutic targets within microglial pathways.
