APOE 4/4 promotes dysfunctional and inflammatory phenotypes concomitant with impaired maturation of hiPSC-derived astrocytes
- 1Cajal Neuroscience Center, CSIC
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.
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BibTeX
@misc{vecino2026apoe,
title = {{APOE 4/4 promotes dysfunctional and inflammatory phenotypes concomitant with impaired maturation of hiPSC-derived astrocytes}},
author = {R. Vecino and E. Diaz-Guerra and E. Arribas-Gonzalez and D. Sanz Gil and F. J. Fernandez Acosta and I. Serra and E. P. Moreno-Jimenez and R. Moratalla and M. Navarrete and C. Vicario},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749463},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749463v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - APOE 4/4 promotes dysfunctional and inflammatory phenotypes concomitant with impaired maturation of hiPSC-derived astrocytes
AU - R. Vecino
AU - E. Diaz-Guerra
AU - E. Arribas-Gonzalez
AU - D. Sanz Gil
AU - F. J. Fernandez Acosta
AU - I. Serra
AU - E. P. Moreno-Jimenez
AU - R. Moratalla
AU - M. Navarrete
AU - C. Vicario
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749463
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749463v1
AB - 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.
ER -