APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice.
Overview
15 affiliations
- Achucarro Basque Center for Neuroscience, Leioa, Spain
- Department of Neurosciences, University of the Basque Country (UPV/EHU), Leioa, Spain
- VIB Center for Brain & Disease Research, Leuven, Belgium
- Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Japan
- Fundacion CIEN, Madrid, Spain
- Center for Cooperative Research in Biosciences (CIC BioGUNE), Science and Technology Park of Bizkaia, 48160 Derio, Spain
- Centre for Networked Biomedical Research on Liver and Digestive Diseases (CIBERehd -ISCIII), Madrid, Spain
- Computational Neuroimaging Lab, Biobizkaia Health Research Institute, Barakaldo, Spain
- IKERBASQUE Basque Foundation for Science, Bilbao, Spain
- Center for Inflammation Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Boston University, Chobanian & Avedisian School of Medicine, Boston, MA, USA
- Department of Genetics and Genomics Sciences, Ronald M. Loeb Center for Alzheimer’s Disease, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- UK Dementia Research Institute, University College London, London, UK
Abstract
Astrocytes and APOE are strongly implicated in Alzheimer’s disease (AD), yet the impact of astrocytes carrying different APOE variants on AD hallmarks remains incompletely understood. Here, we generate a chimeric model of AD by transplanting isogenic APOE3 or APOE4 human induced pluripotent stem cell-derived astrocyte progenitors into neonatal AD mice. Donor cells differentiate into human astrocytes that integrate into the cortex and display morphologies consistent with interlaminar-like astrocytes. APOE3 and APOE4 astrocytes differ in expression of APOE, which associates differentially with Aβ plaques. Notably, APOE3 astrocytes are associated with reduced Aβ burden, Tau pathology, and neuritic dystrophy, whereas APOE4 astrocytes exacerbate these processes. They also induce distinct microglial responses: APOE4 astrocytes enhance microglial clustering around Aβ plaques and promote a disease-associated microglia-like state, whereas APOE3 astrocytes reduce clustering and support a more homeostatic profile. These findings highlight a role for human astrocytes and APOE-dependent astrocyte functions in modulating AD-related pathology.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.
The paper's code and data availability statement is in the Data section.
Tracing map
A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.
Data
No dataset and no data link were found in the paper.
Data and code availability
• Single-cell RNA-seq data have been deposited at GEO GSE335500 and are publicly available. • Microscopy data reported in this paper will be shared by the lead contact upon request. • This paper does not report original code. • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 3, 28 September 2026
- Publisher: — → Cell Press
- Authors: added Amaia M. Arranz (0000-0002-8314-7870); removed Amaia M. Arranz
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 21 authors, 11 keywords, 11 funders, 57 references, 46 RRIDs.
Cite
This paper
Cruz-Sese, J., Mirón-Alcala, M., Alfonso-Triguero, M., Olalde, J., Ruiz, L., Galbis-Gramage, N., Cortes, L., Escobar, L., Preman, P., Snellinx, A., Saito, T., Saido, T. C., Saiz-Aúz, L., Rábano-Gutiérrez, A., Aransay, A. M., Diez, I., Tcw, J., Goate, A., De Strooper, B., . . . Arranz, A. M. (2026). APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice. Cell reports, 45(8), 117803. https://
BibTeX
@article{cruzsese2026apo
author = {Cruz-Sese, Joan and Mirón-Alcala, Marta and Alfonso-Triguero, María and Olalde, Jon and Ruiz, Leire and Galbis-Gramage, Nuria and Cortes, Lorea and Escobar, Laura and Preman, Pranav and Snellinx, An and Saito, Takashi and Saido, Takaomi C. and Saiz-Aúz, Laura and Rábano-Gutiérrez, Alberto and Aransay, Ana M. and Diez, Ibai and Tcw, Julia and Goate, Alison and De Strooper, Bart and Alberdi, Elena and Arranz, Amaia M.},
title = {{APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice}},
journal = {Cell reports},
year = {2026},
month = aug,
volume = {45},
number = {8},
pages = {117803},
publisher = {Cell Press},
issn = {2211-1247},
doi = {10.1016/
url = {https://
pmid = {42570239},
pmcid = {PMC13506673}
}
RIS
TY - JOUR
AU - Cruz-Sese, Joan
AU - Mirón-Alcala, Marta
AU - Alfonso-Triguero, María
AU - Olalde, Jon
AU - Ruiz, Leire
AU - Galbis-Gramage, Nuria
AU - Cortes, Lorea
AU - Escobar, Laura
AU - Preman, Pranav
AU - Snellinx, An
AU - Saito, Takashi
AU - Saido, Takaomi C.
AU - Saiz-Aúz, Laura
AU - Rábano-Gutiérrez, Alberto
AU - Aransay, Ana M.
AU - Diez, Ibai
AU - Tcw, Julia
AU - Goate, Alison
AU - De Strooper, Bart
AU - Alberdi, Elena
AU - Arranz, Amaia M.
TI - APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice
T2 - Cell reports
J2 - Cell Rep
PY - 2026
DA - 2026/
VL - 45
IS - 8
SP - 117803
SN - 2211-1247
PB - Cell Press
DO - 10.1016/
UR - https://
LA - en
ER -
CSL-JSON
{
"id": "10.1016/
"type": "article-journal",
"title": "APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice",
"container-title": "Cell reports",
"author": [
{
"family": "Cruz-Sese",
"given": "Joan"
},
{
"family": "Mirón-Alcala",
"given": "Marta"
},
{
"family": "Alfonso-Triguero",
"given": "María"
},
{
"family": "Olalde",
"given": "Jon"
},
{
"family": "Ruiz",
"given": "Leire"
},
{
"family": "Galbis-Gramage",
"given": "Nuria"
},
{
"family": "Cortes",
"given": "Lorea"
},
{
"family": "Escobar",
"given": "Laura"
},
{
"family": "Preman",
"given": "Pranav"
},
{
"family": "Snellinx",
"given": "An"
},
{
"family": "Saito",
"given": "Takashi"
},
{
"family": "Saido",
"given": "Takaomi C."
},
{
"family": "Saiz-Aúz",
"given": "Laura"
},
{
"family": "Rábano-Gutiérrez",
"given": "Alberto"
},
{
"family": "Aransay",
"given": "Ana M."
},
{
"family": "Diez",
"given": "Ibai"
},
{
"family": "Tcw",
"given": "Julia"
},
{
"family": "Goate",
"given": "Alison"
},
{
"family": "De Strooper",
"given": "Bart"
},
{
"family": "Alberdi",
"given": "Elena"
},
{
"family": "Arranz",
"given": "Amaia M."
}
],
"container-title-short":
"volume": "45",
"issue": "8",
"page": "117803",
"DOI": "10.1016/
"PMID": "42570239",
"PMCID": "PMC13506673",
"ISSN": "2211-1247",
"publisher": "Cell Press",
"URL": "https://
"language": "en",
"issued": {
"date-parts": [
[
2026,
8,
8
]
]
}
}
Similar papers
The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.
- [1] doi:10.1002/exp2.70160
- &
lt;i& gt;RBFOX1& lt;/ i& gt; Dysfunction Unlocks & lt;i& gt;APOE4& lt;/ i& gt;-Associated Microglial Genesis and Exacerbates Alzheimer's Pathology in Human Cerebral Organoids. Journal: Exploration (Beijing, China)In common: Alzheimer's / dementia, cellular / molecular, 5 references - [2] doi:10.1038/s41593-026-02367-0 [code]
- A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.Journal: Nature neuroscienceIn common: Alzheimer's / dementia, cellular / molecular, 6 references
- [3] doi:10.1126/sciadv.aed6825
- SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain.Journal: Science advancesIn common: Alzheimer's / dementia, mouse, cellular / molecular, 5 references
- [4] doi:10.1038/s44321-026-00488-4 [code]
- DeepPlaque: a scalable multimodal platform for Aβ pathology and cell analysis in Alzheimer's disease.Journal: EMBO molecular medicineIn common: Alzheimer's / dementia, cellular / molecular, 5 references
- [5] doi:10.1038/s43587-026-01204-0
- Fibronectin mediates APOE4-driven blood-brain barrier dysfunction in Alzheimer's disease.Journal: Nature agingIn common: Alzheimer's / dementia, mouse, cellular / molecular, 4 references
- [6] doi:10.3390/ijms27135902
- Functional Expression of Nicotinic Receptors on iPSC-Derived Astrocytes and Signalling Disturbances by a Panel of Neonicotinoid Pesticides and Their Metabolites.Journal: International journal of molecular sciencesIn common: cellular / molecular, 4 references
- [7] doi:10.1186/s12974-026-03888-y
- Integrated imaging and molecular profiling reveals APOE4-associated neurovascular and glial disruptions in young adult mice.Journal: Journal of neuroinflammationIn common: Alzheimer's / dementia, mouse, cellular / molecular, 3 references
- [8] doi:10.1126/sciadv.adx0731 [code]
- Targeting glial PD-1/
PD-L1 restores microglial homeostasis and reduces neuronal hyperactivity in an Alzheimer's disease model. Journal: Science advancesIn common: Alzheimer's / dementia, mouse, cellular / molecular, 3 references - [9] doi:10.1128/mbio.01294-26
- Single-cell analysis of Powassan virus-infected brains reveals age-dependent neuroinflammatory crosstalk and progressive Alzheimer's-like APP/
Aβ accumulation. Journal: mBioIn common: Alzheimer's / dementia, mouse, cellular / molecular, 3 references - [10] doi:10.1038/s41593-026-02267-3 [code]
- Spatial proteomic analysis in human Alzheimer's disease brains enables identification of microenvironment-depende
nt microglial cell states. Journal: Nature neuroscienceIn common: Alzheimer's / dementia, cellular / molecular, 3 references
Contribute
The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.
Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.
Claim this paper
Correct its record
Say what each link of this record is, remove the ones that are not the paper's, add the ones that are missing. The correction becomes a new version of the record, in its Versions section.
Request its removal
To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).
Discussion, reproductions, activity
Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.
Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.
Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.