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Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support
Laura Cáceres-Palomo, Elisabeth Sánchez‐Mejías, Laura Trujillo‐Estrada, Juan José Pérez-Moreno, Elba Lopez-Oliva, Tau En Lim, Leah DeFlitch, Serena H. Chang et al.. Journal of Neuroinflammation, 2025-12-12
Topic: Brain proteins, microglia and lab models
Plain-language summary
Alzheimer´s disease (AD) is dominated by a complex cellular pathology which involves most brain cell types with glial cells increasingly recognized as playing fundamental roles in neurodegeneration. Astrocytes, which perform essential functions in preserving brain homeostasis, present a reactive phenotype in the AD brains with still unknown consequences. In this study, we generated and characterized human induced pluripotent stem cell (hiPSC)-derived astrocytes from AD patients harboring the APOE4/4 genotype, the greatest genetic risk factor for late-onset AD. Disease astrocytes showed a reactive phenotype. In addition, they showed altered mitochondrial network including perinuclear clustering of mitochondria, enhanced mitochondrial fusion and higher production of reactive oxygen species which, unexpectedly, were coincident with increased oxidative phosphorylation and glycolysis. As these mitochondrial features are related to the acquisition of cell senescence, we evaluated this at the transcriptome level and found that these AD-derived astrocytes significantly upregulated gene signatures of cellular senescence and displayed a senescence-associated secretory phenotype (SASP). To verify this finding, we observed senescence-related DNA damage response in a significant proportion of cells in the cerebral cortex of AD patients, with most of these cells being astrocytes. Finally, we confirmed that this astrocytic senescent and proinflammatory phenotype is associated with a reduced neuronal support, evidencing that APOE4/4 AD astrocytes present intrinsic features that may compromise brain homeostasis and promote neurodegeneration. Addressing the causes and consequences of this astrocytic dysfunctionality should help to elucidate novel therapeutic targets able to modify the neurodegeneration present in AD.
What this study adds
Evidence grade: Low
In this laboratory study, astrocytes derived from Alzheimer's patients with the APOE4/4 genotype showed a reactive, senescent, and pro-inflammatory state that compromised their support of neurons. These findings are from cell models and human tissue and do not yet show a treatment for people.
Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Cáceres-Palomo, L., Sánchez‐Mejías, E., Trujillo‐Estrada, L., Pérez-Moreno, J. J., Lopez-Oliva, E., Lim, T. E., et al. (2025). Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support. Journal of Neuroinflammation. https://doi.org/10.1186/s12974-025-03607-z
Vancouver
Cáceres-Palomo L, Sánchez‐Mejías E, Trujillo‐Estrada L, Pérez-Moreno JJ, Lopez-Oliva E, Lim TE, et al. Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support. Journal of Neuroinflammation. 2025. doi:10.1186/s12974-025-03607-z. PMID: 41388301.
BibTeX
@article{cacerespalomo2025-41388301,
author = {Cáceres-Palomo, Laura and Sánchez‐Mejías, Elisabeth and Trujillo‐Estrada, Laura and Pérez-Moreno, Juan José and Lopez-Oliva, Elba and Lim, Tau En and DeFlitch, Leah and Chang, Serena H. and others},
title = {{Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support}},
journal = {Journal of Neuroinflammation},
year = {2025},
doi = {10.1186/s12974-025-03607-z},
pmid = {41388301},
url = {https://doi.org/10.1186/s12974-025-03607-z}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- As these mitochondrial features are related to the acquisition of cell senescence, we evaluated this at the transcriptome level and found that these AD-derived astrocytes significantly upregulated gene signatures of cellular senescence and displayed a senescence-associated secretory phenotype (SASP).
- To verify this finding, we observed senescence-related DNA damage response in a significant proportion of cells in the cerebral cortex of AD patients, with most of these cells being astrocytes.
- Finally, we confirmed that this astrocytic senescent and proinflammatory phenotype is associated with a reduced neuronal support, evidencing that APOE4/4 AD astrocytes present intrinsic features that may compromise brain homeostasis and promote neurodegeneration.
Why it matters
In this laboratory study, astrocytes derived from Alzheimer's patients with the APOE4/4 genotype showed a reactive, senescent, and pro-inflammatory state that compromised their support of neurons. These findings are from cell models and human tissue and do not yet show a treatment for people.
Study details
- Evidence strengthLow
How this study scored 44/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Neuroinflammation) |
| Journal's citation record | 2 / 4 | Journal of Neuroinflammation: journal h-index 216 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “ipsc”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 11 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 6.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 11 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Antonia Gutiérrez: h-index 45 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 13 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41388301) |
| Free to read | 2 / 2 | Free to read |
| Total | 44 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1186/s12974-025-03607-z
- PubMed: 41388301
- Original source →
- Free full text: Journal of Neuroinflammation →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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