Homeostatic Microglia Initially Seed and Activated Microglia Later Reshape Amyloid Plaques in Alzheimer's Disease

Baligács, Nóra; Albertini, Giulia; Borrie, Sarah C.; Serneels, Lutgarde; Pridans, Clare; Balusu, Sriram; De Strooper, Bart

doi:10.1038/s41467-024-54779-w

Cited by 123Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Homeostatic Microglia Initially Seed and Activated Microglia Later Reshape Amyloid Plaques in Alzheimer's Disease

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Baligács, Nóra, Albertini, Giulia, Borrie, Sarah C., Serneels, Lutgarde, Pridans, Clare, Balusu, Sriram, De Strooper, Bart·2024·Nature Communications

DOI 10.1038/s41467-024-54779-wPMC PMC11621353

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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 TREM2 R47H/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.

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X34 strongly binds β-sheeted amyloid, labelling both dense plaque cores and surrounding amyloid deposits, with lower intensity in the latter.
“Plaques were characterized using X34, a dye that strongly binds β‐sheeted amyloid, labelling both dense plaque cores and surrounding amyloid deposits, albeit with lower intensity in the latter”
From Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> App NL </scp> ‐G‐F Mice (2026) · cites this paper as Baligács et al. 2024
The Methods (Immunofluorescence and Imaging; page unavailable) describe X34 as a fluorescent beta-sheet-specific amyloid dye, and the Fig. 2 caption identifies X34 staining of fibrillar plaques. The paper does not state that X34 labels surrounding amyloid deposits at lower intensity than dense cores; it instead identifies 82E1 as staining diffuse Aβ aggregates. (LLM, conf=0.85)
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[20]Mancuso, R. et al. Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related amyloid-β pathology. Nat. Neurosci. 27, 886–900 (2024). 38539015 PMC11089003 · DOI · Paper page

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Authors: Baligács, N., Albertini, G., Borrie, S. C., Serneels, L., Pridans, C., Balusu, S., & De Strooper, B.
Affiliations: Vlaams Instituut voor Biotechnologie (BE)
Centre for Inflammation Research (GB)
ORCID: Baligács, Nóra
Albertini, Giulia
Borrie, Sarah C.
Serneels, Lutgarde
Pridans, Clare
Balusu, Sriram
De Strooper, Bart
Venue: Nature Communications
Publisher: Springer Science and Business Media LLC
Published: 2024-12-05
Volume: 15
Issue: 1
Pages: 10634-10634
ISSN: 2041-1723 (ISSN-L)
DOI: 10.1038/s41467-024-54779-w
PMC: PMC11621353
OpenAlex: W4405035908
Cited by: 123
References: 76
Citations by year: 2026: 66 · 2025: 57
FWCI: 19.19
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Nature Communications (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 (KU Leuven) (submittedVersion, cc-by)
RePEc: Research Papers in Economics (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders: Alzheimer's Association
Queen Elisabeth Medical Foundation
European Commission (HORIZON2020, ERC-834682 CELLPHASE_AD, 834682)
Fonds Wetenschappelijk Onderzoek (11PSA24N)
KU Leuven
Vlaams Instituut voor Biotechnologie
Vlaamse regering
Fondation pour la Recherche sur Alzheimer
Fondation Médicale Reine Elisabeth
Medical Research Council (MR/Y014847/1)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords: microglia, Alzheimer's disease, amyloid plaques, neuritic dystrophy, microglial depletion, amyloid clearance, Rag2 knockout mice, amyloid hypothesis
MeSH terms: Alzheimer Disease, Animals, Disease Models, Animal, Female, Homeostasis, Humans, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Receptors, Immunologic, Amyloid beta-Peptides, Microglia, Mice, Plaque, Amyloid

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Homeostatic Microglia Initially Seed and Activated Microglia Later Reshape Amyloid Plaques in Alzheimer's Disease

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