ArticleNeurobiology of disease2022
APOE4 confers transcriptomic and functional alterations to primary mouse microglia.
Article in Neurobiology of disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 77 citations in OpenAlex.
- Review
- Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice.Nature communications · 2026Article
- Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine and reduced Alzheimer's disease risk.Research square · 2026Article
- APOE4 Drives Uniquely Dysfunctional Human Microglial States in Alzheimer's Disease.bioRxiv : the preprint server for biology · 2026Article
- Alzheimer's Disease Risk AllelebioRxiv : the preprint server for biology · 2026Article
- Viral Mimicry of Alzheimer's Disease: Innate Sensing of Self-Nucleic Acids as a Driver of Glial Senescence.Journal of molecular neuroscience : MN · 2026Review
- MEF2C controls lysosomal and lipid clearance programs linked to Alzheimer's disease risk in macrophages.Research square · 2026Article
- ApoE4 Drives Microglial Lipid Dysregulation in Alzheimer's Disease via Epigenetic Reprogramming of the Asxl1/LXRα-H3K4me3 Axis.Journal of neuroinflammation · 2026Article
- Is there a role for apolipoprotein E in perinatal brain injury?Molecular and cellular pediatrics · 2026Review
- Integrated Stress Response Signatures Drive Monocyte Dysfunction in GBA1- and LRRK2-Linked Parkinson's Disease.Research square · 2026Article
- Spatially resolved transcriptome-metabolome integration reveals region-specific glial lipid dysregulation associated with Alzheimer's pathology.bioRxiv : the preprint server for biology · 2026Article
- Microglial phagocytosis in Alzheimer disease.Nature reviews. Neurology · 2026Review
- Elevated Apolipoprotein E Expression in Hippocampal Microglia Drives Temporal Lobe Epilepsy Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Dysregulated mRNA Translation in Alzheimer's Disease: Mechanisms, Therapeutic Opportunities, and Challenges for Clinical Translation.Clinical interventions in aging · 2026Review
- ApoE4 Homozygosity Is Associated With Increased Microglia Activation in Fatal COVID-19.Neuropathology : official journal of the Japanese Society of Neuropathology · 2025Article
- APOE-Targeted Therapeutics for Alzheimer's Disease.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Review
- Integrated Stress Response Signatures Drive Monocyte Dysfunction inmedRxiv : the preprint server for health sciences · 2025Article
- APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses.Neurobiology of disease · 2025Article
- Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro.Cell reports · 2025Article
- The APOE-Microglia Axis in Alzheimer's Disease: Functional Divergence and Therapeutic Perspectives-A Narrative Review.Brain sciences · 2025Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Common genetic variants in more than forty loci modulate risk for Alzheimer's disease (AD). AD risk alleles are enriched within enhancers active in myeloid cells, suggesting that microglia, the brain-resident macrophages, may play a key role in the etiology of AD. A major genetic risk factor for AD is Apolipoprotein E (APOE) genotype, with the ε4/ε4 (E4) genotype increasing risk for AD by approximately 15 fold compared to the most common ε3/ε3 (E3) genotype. However, the impact of APOE genotype on microglial function has not been thoroughly investigated. To address this, we cultured primary microglia from mice in which both alleles of the mouse Apoe gene have been humanized to encode either human APOE ε3 or APOE ε4. Relative to E3 microglia, E4 microglia exhibit altered morphology, increased endolysosomal mass, increased cytokine/chemokine production, and increased lipid and lipid droplet accumulation at baseline. These changes were accompanied by decreased translation and increased phosphorylation of eIF2ɑ and eIF2ɑ-kinases that participate in the integrated stress response, suggesting that E4 genotype leads to elevated levels of cellular stress in microglia relative to E3 genotype. Using live-cell imaging and flow cytometry, we also show that E4 microglia exhibited increased phagocytic uptake of myelin and other substrates compared to E3 microglia. While transcriptomic profiling of myelin-challenged microglia revealed a largely overlapping response profile across genotypes, differential enrichment of genes in interferon signaling, extracellular matrix and translation-related pathways was identified in E4 versus E3 microglia both at baseline and following myelin challenge. Together, our results suggest E4 genotype confers several important functional alterations to microglia even prior to myelin challenge, providing insight into the molecular and cellular mechanisms by which APOE4 may increase risk for AD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.