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<i>RBFOX1</i> Dysfunction Unlocks <i>APOE4</i>-Associated Microglial Genesis and Exacerbates Alzheimer's Pathology in Human Cerebral Organoids.

Overview

Authors: Bowen Zhang1, Changjie Shi1, Jiayi Zhao1, Qiuhong Hua1, Houchun Zhang1, Hailin Gao1, Yuanyuan Qian1, Jiaxue Cha1, Jing Li1, Jiayao Chen1, Tae‐Hyung Kim2, Jianhuang Xue3, Yujun Hou1, Ru Zhang1
ORCID iDs: Tae‐Hyung Kim, Jianhuang Xue, Yujun Hou
  1. Institute For Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
  2. Department of Biomedical Engineering, Institute For Cross‐disciplinary Studies (ICS), Sungkyunkwan University (SKKU), Suwon, Gyeonggi, Republic of Korea
  3. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital Affiliated to Tongji University, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
Institutions: Tongji University (China); Shanghai East Hospital (China); Sungkyunkwan University (South Korea)
Journal: Exploration (Beijing, China), volume 6, issue 2, article 70160
Dates: received 13 April 2025; accepted 16 March 2026; published online 2 April 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1002/exp2.70160 · PMID 42016760 · PMCID PMC13094536 · OpenAlex W7148627413
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics
Keywords: Alzheimer's disease, APOE4, microglia generation, organoids, RBFOX1
Topic: Neuroinflammation and Neurodegeneration Mechanisms (Neurology, Neuroscience), according to OpenAlex
Funding: Natural Science Foundation of Shanghai (23ZR1465600); National Natural Science Foundation of China (82471614, #82171405); Ministry of Science and Technology of the People's Republic of China (2017YFA0104002); Fundamental Research Funds for the Central Universities (22120240435)
Citations: not cited yet (Europe PMC); 107 references in the paper

Abstract

Alzheimer's disease (AD) pathogenesis is strongly influenced by APOE4, though how cooperative genetic factors modulate this relationship remains unclear. While genomic studies have tentatively linked RBFOX1 to AD susceptibility, its functional synergy with APOE4 has never been experimentally defined. We engineered APOE3 or APOE4 isogenic human cerebral organoids with CRISPR/Cas9‐mediated RBFOX1 knockout. Remarkably, RBFOX1 depletion selectively triggered robust microglial generation exclusively in APOE4 organoids. Time‐course gene expression revealed that this APOE4‐specific effect correlated with prolonged mesodermal priming during early embryoid body differentiation, creating a permissive niche for microglial lineage specification. The emergent microglia exhibited pronounced neurotoxic phenotypes, including pro‐inflammatory factor secretion, synaptic architecture remodeling, and lipid droplet accumulation in organoids. These changes coincided with aggravated Tau hyperphosphorylation and electrophysiological abnormalities, collectively mirroring multifaceted AD pathology. Our findings establish RBFOX1 as a potential AD protective factor, a critical suppressor of APOE4‐glia crosstalk, and demonstrate that its loss unleashes a microglia‐mediated neurodegenerative cascade. By developing cerebral organoids with autonomous microglial networks, we present a platform capable of modeling genotype‐dependent neuron‐glia interactions in AD, opening new avenues for mechanistic and therapeutic exploration.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

Data Availability Statement

Raw data for all sequencing experiments have been deposited at the Gene Expression Omnibus (GEO) under the accession number GSE292560. To review GEO accession GSE292560: Go to https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE292560, Enter token gzylskyirzwhjmf into the box.

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 2, 28 September 2026

  • Funding: added Natural Science Foundation of Shanghai: 23ZR1465600; National Natural Science Foundation of China: 82471614, #82171405; Ministry of Science and Technology of the People's Republic of China: 2017YFA0104002; Fundamental Research Funds for the Central Universities: 22120240435

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 5 keywords, 107 references.

Cite

This paper

Zhang, B., Shi, C., Zhao, J., Hua, Q., Zhang, H., Gao, H., Qian, Y., Cha, J., Li, J., Chen, J., Kim, T., Xue, J., Hou, Y., & Zhang, R. (2026). <i>RBFOX1</i> Dysfunction Unlocks <i>APOE4</i>-Associated Microglial Genesis and Exacerbates Alzheimer's Pathology in Human Cerebral Organoids. Exploration (Beijing, China), 6(2), 70160. https://doi.org/10.1002/exp2.70160

BibTeX

@article{zhang2026lt,
author = {Zhang, Bowen and Shi, Changjie and Zhao, Jiayi and Hua, Qiuhong and Zhang, Houchun and Gao, Hailin and Qian, Yuanyuan and Cha, Jiaxue and Li, Jing and Chen, Jiayao and Kim, Tae‐Hyung and Xue, Jianhuang and Hou, Yujun and Zhang, Ru},
title = {{\<i\>RBFOX1\</i\> Dysfunction Unlocks \<i\>APOE4\</i\>-Associated Microglial Genesis and Exacerbates Alzheimer's Pathology in Human Cerebral Organoids}},
journal = {Exploration (Beijing, China)},
year = {2026},
month = apr,
volume = {6},
number = {2},
pages = {70160},
publisher = {Wiley},
issn = {2766-8509},
doi = {10.1002/exp2.70160},
url = {https://doi.org/10.1002/exp2.70160},
pmid = {42016760},
pmcid = {PMC13094536}
}

RIS

TY - JOUR
AU - Zhang, Bowen
AU - Shi, Changjie
AU - Zhao, Jiayi
AU - Hua, Qiuhong
AU - Zhang, Houchun
AU - Gao, Hailin
AU - Qian, Yuanyuan
AU - Cha, Jiaxue
AU - Li, Jing
AU - Chen, Jiayao
AU - Kim, Tae‐Hyung
AU - Xue, Jianhuang
AU - Hou, Yujun
AU - Zhang, Ru
TI - <i>RBFOX1</i> Dysfunction Unlocks <i>APOE4</i>-Associated Microglial Genesis and Exacerbates Alzheimer's Pathology in Human Cerebral Organoids
T2 - Exploration (Beijing, China)
J2 - Exploration (Beijing)
PY - 2026
DA - 2026/04/02
VL - 6
IS - 2
SP - 70160
SN - 2766-8509
PB - Wiley
DO - 10.1002/exp2.70160
UR - https://doi.org/10.1002/exp2.70160
LA - en
ER -

CSL-JSON

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