{
  "abstract": "Alzheimer's disease (AD) is the leading cause of dementia in the aging population, with the {varepsilon}4 allele of apolipoprotein E (APOE) being the strongest genetic risk factor. Although astrocytes are a major source of APOE, how APOE alleles affect astrocyte maturation and function remains unclear. We generated human induced pluripotent stem cell (hiPSC)-derived astrocytes from AD patients carrying {varepsilon}3/{varepsilon}3 and {varepsilon}4/{varepsilon}4 alleles and from healthy controls (HC). We also used isogenic gene-edited hiPSC lines homozygous for each APOE allele and an APOE knock-out line to identify allele-specific phenotypes and distinguish gain- from loss-of-function mechanisms. APOE 4/4 astrocyte cultures showed significant reductions in GFAP- and S100{beta}-positive cell percentages compared to APOE 2/2 and APOE 3/3, with no changes in GLT-1- and AQP4-positive cells. Astrocytes of all genotypes responded to IL-1{beta} + TNF by increasing proinflammatory cytokine expression and release, and to both IL-1{beta} + TNF and A{beta}1-42 by changing morphology, with APOE 4/4 astrocytes showing increased IL6 mRNA and morphological branching upon IL-1{beta} + TNF stimulation. Notably, under basal conditions, APOE 4/4 astrocytes showed significant reductions in glutamate uptake capacity and cell size alongside increased IL-6 release and CXCL3 mRNA expression. In A{beta}1-42 uptake experiments, the proportion of A{beta}+ astrocytes was higher in APOE 4/4 than in APOE KO cultures. Most phenotypes were absent in APOE KO astrocytes, suggesting that the effects of APOE 4/4 were predominantly mediated through gain-of-function mechanisms. Our results indicate that APOE 4/4 alters astrocyte morphological and molecular maturation while promoting inflammation, disturbing glutamate and A{beta} handling under basal conditions. It suggests that APOE {varepsilon}4/{varepsilon}4 genotype disrupts astrocyte development and key processes of cellular homeostasis early in Alzheimer's disease etiopathology.",
  "abstract_shown": true,
  "affiliations": [
    "Cajal Neuroscience Center, CSIC"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "R. Vecino"
    },
    {
      "name": "E. Diaz-Guerra"
    },
    {
      "name": "E. Arribas-Gonzalez"
    },
    {
      "name": "D. Sanz Gil"
    },
    {
      "name": "F. J. Fernandez Acosta"
    },
    {
      "name": "I. Serra"
    },
    {
      "name": "E. P. Moreno-Jimenez"
    },
    {
      "name": "R. Moratalla"
    },
    {
      "name": "M. Navarrete"
    },
    {
      "affs": [
        0
      ],
      "name": "C. Vicario"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3987kdt05xtzv.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.04.749463",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749463v1.full",
  "id": "3987kdt05xtzv",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749463v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749463v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3987kdt05xtzv.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:56Z",
      "native_id": "10.64898/2026.09.04.749463",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749463v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "APOE 4/4 promotes dysfunctional and inflammatory phenotypes concomitant with impaired maturation of hiPSC-derived astrocytes",
  "title_text": "APOE 4/4 promotes dysfunctional and inflammatory phenotypes concomitant with impaired maturation of hiPSC-derived astrocytes",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:56Z",
  "url": "https://research.draconitic.com/paper/3987kdt05xtzv",
  "venue": "bioRxiv",
  "versions": []
}