Murphy, Kitty B;
Hu, Di;
Wolfs, Leen;
Rohde, Susan K;
Fauro, Gonzalo Leguia;
Geric, Ivana;
Mancuso, Renzo;
... Marzi, Sarah J; + view all
(2025)
The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia xenografted into a mouse model of Alzheimer’s disease.
Nature Communications
, 16
, Article 4883. 10.1038/s41467-025-60099-4.
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Abstract
Microglia play a key role in the response to amyloid beta in Alzheimer’s disease (AD). In this context, the major transcriptional response of microglia is the upregulation of APOE, the strongest late-onset AD risk gene. Of its three isoforms, APOE2 is thought to be protective, while APOE4 increases AD risk. We hypothesised that the isoforms change gene regulatory patterns that link back to biological function by shaping microglial transcriptomic and chromatin landscapes. We use RNA- and ATAC-sequencing to profile gene expression and chromatin accessibility of human microglia xenotransplantated into the brains of male APPNL-G-F mice. We identify widespread transcriptomic and epigenomic differences which are dependent on APOE genotype and are corroborated across the profiling assays. Our results indicate that impaired microglial proliferation, migration and immune responses may contribute to the increased risk for late-onset AD in APOE4 carriers, while increased phagocytic capabilities and DNA-binding of the vitamin D receptor in APOE2 microglia may contribute to the isoform’s protective role.
| Type: | Article |
|---|---|
| Title: | The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia xenografted into a mouse model of Alzheimer’s disease |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41467-025-60099-4 |
| Publisher version: | https://doi.org/10.1038/s41467-025-60099-4 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10212624 |
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