Mancuso, R;
Fattorelli, N;
Martinez-Muriana, A;
Davis, E;
Wolfs, L;
Van Den Daele, J;
Geric, I;
... De Strooper, B; + view all
(2024)
Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related amyloid-β pathology.
Nature Neuroscience
10.1038/s41593-024-01600-y.
(In press).
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Abstract
Microglia are central players in Alzheimer’s disease pathology but analyzing microglial states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single-cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild-type controls. Xenografted human microglia adopt a disease-associated profile similar to that seen in mouse microglia, but display a more pronounced human leukocyte antigen or HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine cytokine response microglia or CRM response to oligomeric Aβ oligomers. Genetic deletion of TREM2 or APOE as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other Alzheimer’s disease risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in a multipronged response to Alzheimer’s disease-related pathology, which should be taken into account in translational studies.
| Type: | Article |
|---|---|
| Title: | Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related amyloid-β pathology |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41593-024-01600-y |
| Publisher version: | http://dx.doi.org/10.1038/s41593-024-01600-y |
| Language: | English |
| Additional information: | Open Access 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/10190313 |
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