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

Nóra Baligács, Giulia Albertini, Sarah C. Borrie, Lutgarde Serneels, Clare Pridans, Sriram Balusu and Bart Strooper ()
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Nóra Baligács: Flanders Institute for Biotechnology (VIB)
Giulia Albertini: Flanders Institute for Biotechnology (VIB)
Sarah C. Borrie: Flanders Institute for Biotechnology (VIB)
Lutgarde Serneels: Flanders Institute for Biotechnology (VIB)
Clare Pridans: University of Edinburgh Centre for Inflammation Research
Sriram Balusu: Flanders Institute for Biotechnology (VIB)
Bart Strooper: Flanders Institute for Biotechnology (VIB)

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54779-w

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