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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer's Disease
Nóra Baligács1,2, Giulia Albertini1,2, Sarah C Borrie1,2
1Centre for Brain and Disease Research, Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
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.
Insights
Microglia initiate amyloid plaque formation in Alzheimer's disease (AD), contrary to some views. Their depletion reduces plaques, but later stages may benefit from their presence, complicating AD therapeutic strategies.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- The role of microglia in Alzheimer's disease (AD) amyloid cascade is debated.
- Conflicting findings exist regarding microglia's direct impact on amyloid-beta (Aβ) plaque development.
Purpose of the Study:
- To clarify the precise role of microglia in the initiation and progression of amyloid pathology in AD.
- To investigate the impact of microglial depletion and transplantation on Aβ plaque formation and associated neurotoxicity.
Main Methods:
- Utilized genetic and pharmacological approaches for microglial depletion in AD models.
- Employed microglia transplantation studies to assess their role in Aβ plaque restoration.
- Analyzed the effects of TREM2 mutation and adaptive immune depletion on microglial function in AD.
Main Results:
- Microglia depletion before Aβ deposition reduced plaque numbers and neuritic dystrophy, confirming their role in plaque initiation.
- Transplanted human microglia restored Aβ plaque formation.
- Microglia depletion reduced insoluble Aβ but not soluble Aβ, challenging clearance theories.
- In later stages, microglial depletion worsened plaque compaction and increased neuritic dystrophy, suggesting a protective role.
- TREM2R47H/R47H mutation in human microglia exacerbated plaque pathology.
Conclusions:
- Microglia are key drivers in initiating amyloid cascade pathology in Alzheimer's disease.
- The findings challenge the notion of microglia solely as Aβ clearers and suggest a complex, stage-dependent role.
- Optimal therapeutic strategies for AD may need to consider the dual role of microglia, balancing initiation and potential later-stage protection.
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