A multi-pronged human microglia response to Alzheimer’s disease Aβ pathology
Open accessAbstract
Microglial activation and neuroinflammation are initial steps in the pathogenesis of Alzheimer’s disease (AD). However, studies in mouse models and human postmortem samples have yielded divergent results regarding microglia cell states relevant to AD. Here, we investigate 127,000 single cell expression profiles of human microglia isolated freshly from a xenotransplantation model for early AD. While human microglia adopt a disease-associated (DAM) profile, they display a much more pronounced HLA-cell state related to antigen presentation in response to amyloid plaques. In parallel, a distinctive pro-inflammatory cytokine and chemokine CRM response is mounted against oligomeric amyloid-β. TREM2 and, to a lesser extent, APOE polymorphisms, modulate the response of microglia to amyloid-β plaques, in contrast with the response to oligomeric Aβ. Specific polygenic risk genes are enriched in each branch of these multi-pronged response of human microglia to amyloid pathology (ARM). ARM responses can be captured in post-mortem studies when reanalyzed in light of this novel, comprehensive data set. In conclusion, therapeutic strategies targeting microglia in AD need to carefully assess how they affect the different cell states, as the overall balance between distinct microglial profiles might determine a protective or damaging outcome.
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Pseudo-time trajectories from control and AD nuclei set Micro1 as start; homeostatic (Micro1) to GPNMB_EYA2/LPL_CD83 (Micro2) and CRM_CCL3 (Micro4) responses were two independent activation routes; Micro3 branched into a third route.
“We set Micro1 as the start of the pseudo-time as it most highly expressed homeostatic markers such as P2RY12 and CX3CR1. Homeostatic (Micro1) to GPNMB_EYA2/LPL_CD83 (Micro2) and CRM_CCL3 (Micro4) responses were found to be two independent activation routes mirroring the observations in a recent pre-print [47]. Micro3 branched into a third route of the trajectory (Fig. 7a).”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [47]
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ResultA single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain
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Lessons from ex vivo and in vitro models in microglia research
Cserép, C., Berki, P., Mars, M., Pósfai, B., Pasterkamp, R. J., Benkő, S., & Dénes, Á. (2025) · Trends in Neurosciences · doi:10.1016/j.tins.2025.10.004 · Cited by 5 · see citing works
Advancing Alzheimer’s research by improving disease modeling of secondary tauopathy
Roy, E. R., & Cao, W. (2025) · npj Dementia · doi:10.1038/s44400-025-00044-w · Cited by 4 · see citing works
Ahuja, K., Ramezankhani, R., Wang, X., Burg, T., Amos, G., Neyrinck, K., Silva, A., Arekatla, G., Cassidy, E. E., Nami, F., et al. (2026) · Stem Cell Reviews and Reports · doi:10.1007/s12015-026-11061-4 · Cited by 4 · see citing works
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Masrori, P., Bijnens, B., Davie, K., Poovathingal, S. K., Storm, A., Hersmus, N., Fumagalli, L., Bosch, L. V. D., Fiers, M. W. E. J., Thal, D. R., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.26.513909 · Cited by 4 · see citing works
Self-citationConserved phenotype and function of human brain border-associated macrophages in iPSC-derived modelsPreprint
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PU.1 restores microglial dysfunction caused by C9ORF72 repeat expansions in neural organoids
Ljubikj, T., Mars, M., van der Geest, A. T., Jakobs, C. E., Bessler, N., Donega, V., van den Oetelaar, X. P. R. M., de Wit, M., & Pasterkamp, R. J. (2025) · Brain · doi:10.1093/brain/awaf340 · Cited by 4 · see citing works
- Authors
- Mancuso, R., Fattorelli, N., Martinez-Muriana, A., Davis, E., Wolfs, L., Van Den Daele, J., Geric, I., Preman, P., Serneels, L., Poovathingal, S., Balusu, S., Verfaille, C., Fiers, M., & De Strooper, B.
- Affiliations
- University of Antwerp (BE)
- Vlaams Instituut voor Biotechnologie (BE)
- UK Dementia Research Institute (GB)
- Corresponding author
- Mancuso, Renzo
- ORCID
- Venue
- Nature Neuroscience
- Publisher
- openRxiv
- Published
- 2022-07-07
- Volume
- 27
- Issue
- 5
- Pages
- 886-900
- ISSN
- 1097-6256 (ISSN-L)
- PMC
- PMC11089003
- OpenAlex
- W4393225316
- Cited by
- 169
- References
- 67
- Citations by year
- 2026: 76 · 2025: 57 · 2024: 30 · 2023: 3 · 2022: 3
- FWCI
- 25.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Nature Neuroscience (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion, cc-by)
- Lirias (submittedVersion, cc-by)
- Funders
- Alzheimer's Association (AARF-20-684397)
- BrightFocus Foundation (A2021034S)
- UK Research and Innovation (MR/Y014847/1)
- Alzheimer's Society
- Queen Elisabeth Medical Foundation
- European Commission (HORIZON2020, ERC-834682 CELLPHASE_AD, 834682, 2022-2025)
- Fonds Wetenschappelijk Onderzoek (G0C9219N, G0K9422N, 1122423N, 12ZX621N, 1139520N, G056022N, S001221N)
- KU Leuven
- Vlaams Instituut voor Biotechnologie
- Universiteit Antwerpen (FFB210307)
- Vlaamse regering
- UK Dementia Research Institute
- Fondation pour la Recherche sur Alzheimer
- Fondation Médicale Reine Elisabeth
- Horizon 2020 Framework Programme
- Medical Research Council (MR/Y014847/1)
- H2020 Marie Skłodowska-Curie Actions (HORIZON2020)
- HORIZON EUROPE European Research Council (101041867)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- microglia, Alzheimer's disease, amyloid-beta, xenotransplantation, single-cell transcriptomics, disease-associated microglia, HLA, antigen presentation, amyloid plaques, TREM2, apolipoprotein E, inflammatory cytokines, chemokines, amyloid-beta oligomers
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain, Humans, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Amyloid beta-Peptides, Microglia, Mice, Plaque, Amyloid, Transcriptome, Heterografts
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