ArticleJournal of neuroinflammation2025
Inflammation-induced lysosomal dysfunction in human iPSC-derived microglia is exacerbated by APOE 4/4 genotype.
Article in Journal of neuroinflammation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The role of APOE ε4 in modulating the relationship between non-genetic risk factors and dementia: a system review and meta-analysis.Journal of neurology · 2025Pooled it
- Review
- Cross-tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Human Stem Cell-Derived Models of the Alzheimer's Disease Neuroimmune System.International journal of molecular sciences · 2026Review
- Article
- Reshaping the immune landscape: next-generation microglia-targeted therapies for Alzheimer's disease.Biological research · 2026Review
- Microglial checkpoint collapse in Alzheimer's disease: a tri-axial framework for biomarker-informed neuroimmune therapy.Journal of neuroinflammation · 2026Review
- PYGL-driven glycogenolysis impairs microglial autophagic fluxActa pharmaceutica Sinica. B · 2026Article
- The Dual Role of Glial Extracellular Vesicles in Neurodegeneration: Insights from iPSC-Based Models.International journal of molecular sciences · 2026Review
- Lysosomal homeostasis at the crossroads of neurodegeneration.The Journal of clinical investigation · 2026Review
- Apolipoprotein E Deficiency Impairs Human Microglial Proliferation Accompanied by Elevated Cellular Oxidative Stress.Journal of cellular and molecular medicine · 2026Article
- Association between apolipoprotein E gene polymorphisms and the effects of high-intensity interval training on body composition in university students.Frontiers in nutrition · 2026Article
- Nutritional substrates and microglial metabolic fitness in brain aging and Alzheimer's disease: from lipid handling to TREM2-linked translation.Frontiers in nutrition · 2026Review
- Neuronal APOE4 drives damaging lipid accumulation via contact-dependent neuron-oligodendrocyte-microglia interaction in Alzheimer's disease.bioRxiv : the preprint server for biology · 2025Article
- APPswe mutation causes functional deficits in endothelial cells generated by transient ETV2 overexpression in human iPSCs.Fluids and barriers of the CNS · 2025Article
- Potential of phytochemicals in the treatment of Alzheimer disease by modulating lysosomal dysfunction: a systematic review.Chinese medicine · 2025Review
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Authors and funding
17 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe ε4 isoform of apolipoprotein E (ApoE) is the most significant genetic risk factor for Alzheimer's disease. Glial cells are the main source of ApoE in the brain, and in microglia, the ε4 isoform of ApoE has been shown to impair mitochondrial metabolism and the uptake of lipids and Aβ42. However, whether the ε4 isoform alters autophagy or lysosomal activity in microglia in basal and inflammatory conditions is unknown.
methodsAltogether, microglia-like cells (iMGs) from eight APOE3/3 and six APOE4/4 human induced pluripotent stem cell (iPSC) lines were used in this study. The responses of iMGs to Aβ42, LPS and IFNγ were studied by metabolomics, proteomics, and functional assays.
resultsHere, we demonstrate that iMGs with the APOE4/4 genotype exhibit reduced basal pinocytosis levels compared to APOE3/3 iMGs. Inflammatory stimulation with a combination of LPS and IFNγ or Aβ42 induced PI3K/AKT/mTORC signaling pathway, increased pinocytosis, and blocked autophagic flux, leading to the accumulation of sequestosome 1 (p62) in both APOE4/4 and APOE3/3 iMGs. Exposure to Aβ42 furthermore caused lysosomal membrane permeabilization, which was significantly stronger in APOE4/4 iMGs and positively correlated with the secretion of the proinflammatory chemokine IL-8. Metabolomics analysis indicated a dysregulation in amino acid metabolism, primarily L-glutamine, in APOE4/4 iMGs.
conclusionsOverall, our results suggest that inflammation-induced metabolic reprogramming places lysosomes under substantial stress. Lysosomal stress is more detrimental in APOE4/4 microglia, which exhibit endo-lysosomal defects.
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