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Updated: Oct 14, 2025
Author Spotlight: Exploring Sex-Specific Glial Signatures and Therapeutic Leads for Alzheimer's Disease
Published on: May 20, 2024
Microglial transcription profiles in mouse and human are driven by APOE4 and sex
V Alexandra Moser1, Michael J Workman1, Samantha J Hurwitz1
1Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Abstract:
Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). APOE4 is known to affect the function of microglia, but to what extent this gene drives microglial gene expression has thus far not been examined. Using a transgenic mouse model of AD that expresses human APOE, we identify a unique transcriptional profile associated with APOE4 expression. We also show a sex and APOE interaction, such that both female sex and APOE4 drive expression of this gene profile. We confirm these findings in human cells, using microglia derived from induced pluripotent stem cells (iMGL). Moreover, we find that these interactions are driven in part by genes related to metal processing, and we show that zinc treatment has APOE genotype-dependent effects on iMGL. These data identify a sex- and APOE4-associated microglial transcription profile and highlight the importance of considering interactive risk factors such as sex and environmental exposures.
Insights
The strongest Alzheimer's risk gene, Apolipoprotein E4 (APOE4), alters microglial gene expression, particularly in females. This APOE4-driven profile involves metal processing and is influenced by zinc, suggesting interactive risk factors in Alzheimer's disease.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Apolipoprotein E4 (APOE4) is the primary genetic risk factor for sporadic Alzheimer's disease (AD).
- APOE4's impact on microglial function is recognized, but its specific effects on microglial gene expression remain largely unexamined.
Purpose of the Study:
- To investigate the transcriptional profile driven by APOE4 expression in microglia.
- To explore the interaction between sex and APOE genotype on microglial gene expression.
- To identify potential mechanisms, such as metal processing, underlying these effects.
Main Methods:
- Utilized a transgenic mouse model expressing human APOE to analyze microglial transcriptional profiles.
- Validated findings in human induced pluripotent stem cell-derived microglia (iMGL).
- Examined the role of metal processing genes and the effect of zinc treatment on iMGL.
Main Results:
- Identified a unique transcriptional profile associated with APOE4 expression in microglia.
- Demonstrated a significant interaction between female sex and APOE4 in driving this gene expression profile.
- Found that genes related to metal processing are involved, and zinc treatment affects iMGL in an APOE genotype-dependent manner.
Conclusions:
- A distinct microglial transcriptional profile is associated with APOE4 and is modulated by sex.
- Metal processing pathways and environmental factors like zinc may interact with APOE genotype in AD pathogenesis.
- Highlights the importance of considering interactive risk factors, including sex and environmental exposures, in Alzheimer's disease research.
