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Updated: May 6, 2026
Microglia as a Surrogate Biosensor to Determine Nanoparticle Neurotoxicity
Published on: October 25, 2016
Microglia aggregates define distinct immune and neurodegenerative niches in Alzheimer's disease hippocampus
Sonja Fixemer1,2, Mónica Miranda de la Maza1,2,3,4, Gaël Paul Hammer2,3
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belval, Luxembourg.
Abstract:
In Alzheimer's disease (AD), microglia form distinct cellular aggregates that play critical roles in disease progression, including Aβ plaque-associated microglia (PaM) and the newly identified coffin-like microglia (CoM). PaM are closely associated with amyloid-β (Aβ) plaques, while CoM are enriched in the pyramidal layer of the CA2/CA1 hippocampal subfields, where they frequently engulf neurons and associate with tau-positive tangles and phosphorylated α-synuclein. To elucidate the role of these microglial subtypes, we employed high-content neuropathology, integrating Deep Spatial Profiling (DSP), multiplex chromogenic immunohistochemistry and confocal microscopy, to comprehensively map and characterise their morphological and molecular signatures, as well as their neuropathological and astrocytic microenvironments, in AD and control post-mortem samples. PaM and PaM-associated astrocytes exhibited signatures related to complement system pathways, ErbB signalling, and metabolic and neurodegenerative processes. In contrast, CoM displayed markers associated with protein degradation and immune signalling pathways, including STING, TGF-β, and NF-κB. While no direct association between CD8 + T cells and either microglial type was observed, CD163 + perivascular macrophages were frequently incorporated into PaM. These findings provide novel insights into the heterogeneity of microglial responses, in particular their distinct interactions with astrocytes and infiltrating immune cells, and shed light on specific neurodegenerative hotspots and their implications for hippocampal deterioration in AD.
Insights
Alzheimer's disease features distinct microglia types, plaque-associated (PaM) and coffin-like (CoM), with unique roles. PaM interact with astrocytes via complement pathways, while CoM involve immune signaling, impacting hippocampal health.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's immune cells, exhibit diverse responses in Alzheimer's disease (AD).
- Distinct microglial subtypes, plaque-associated microglia (PaM) and coffin-like microglia (CoM), have been identified, suggesting specialized functions in AD pathogenesis.
- Understanding these microglial subtypes and their interactions is crucial for elucidating AD progression and identifying therapeutic targets.
Purpose of the Study:
- To comprehensively map and characterize the morphological and molecular signatures of PaM and CoM in Alzheimer's disease.
- To investigate the neuropathological and astrocytic microenvironments associated with these distinct microglial subtypes.
- To elucidate the specific roles and interactions of PaM and CoM in AD-related hippocampal deterioration.
Main Methods:
- High-content neuropathology utilizing Deep Spatial Profiling (DSP).
- Multiplex chromogenic immunohistochemistry and confocal microscopy on post-mortem AD and control brain samples.
- Integrated analysis of microglial morphology, molecular signatures, and surrounding cellular and molecular milieu.
Main Results:
- PaM and associated astrocytes showed signatures linked to complement pathways, ErbB signaling, metabolism, and neurodegeneration.
- CoM exhibited markers related to protein degradation and immune signaling, including STING, TGF-β, and NF-κB.
- CD163+ perivascular macrophages were found within PaM, while CD8+ T cells showed no direct association with either microglial type.
Conclusions:
- Microglial responses in AD are heterogeneous, with PaM and CoM representing distinct functional states.
- PaM engage in complement-mediated pathways and metabolic processes, interacting with astrocytes and perivascular macrophages.
- CoM are involved in protein degradation and immune signaling, contributing to neuroinflammation and hippocampal pathology in AD.
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