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Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer’s Disease

Baligacs, Nora; Albertini, Giulia; Borrie, Sarah C; Serneels, Lutgarde; Pridans, Clare; Balusu, Sriram; De Strooper, Bart; (2024) Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer’s Disease. Nature Communications , 15 , Article 10634. 10.1038/s41467-024-54779-w. Green open access

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Abstract

The role of microglia in the amyloid cascade of Alzheimer’s disease (AD) is debated due to conflicting findings. Using a genetic and a pharmacological approach we demonstrate that depletion of microglia before amyloid-β (Aβ) plaque deposition, leads to a reduction in plaque numbers and neuritic dystrophy, confirming their role in plaque initiation. Transplanting human microglia restores Aβ plaque formation. While microglia depletion reduces insoluble Aβ levels, soluble Aβ concentrations stay consistent, challenging the view that microglia clear Aβ. In later stages, microglial depletion decreases plaque compaction and increases neuritic dystrophy, suggesting a protective role. Human microglia with the TREM2R47H/R47H mutation exacerbate plaque pathology, emphasizing the importance of non-reactive microglia in the initiation of the amyloid cascade. Adaptive immune depletion (Rag2-/-) does not affect microglia’s impact on plaque formation. These findings clarify conflicting reports, identifying microglia as key drivers of amyloid pathology, and raise questions about optimal therapeutic strategies for AD.

Type: Article
Title: Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer’s Disease
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-024-54779-w
Publisher version: https://doi.org/10.1038/s41467-024-54779-w
Language: English
Additional information: © The Author(s), 2025. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Keywords: Alzheimer's disease, Microglia
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/10207808
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