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Updated: Nov 4, 2025
Correlative Light and Electron Microscopy to Study Microglial Interactions with β-Amyloid Plaques
Published on: June 1, 2016
Transcriptional signature in microglia associated with Aβ plaque phagocytosis
Alexandra Grubman1,2,3, Xin Yi Choo4,5,6,7, Gabriel Chew8
1Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia. alexandra.grubman@monash.edu.
Abstract:
The role of microglia cells in Alzheimer's disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4+) and non-containing (XO4-) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4+ microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4+ microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4- microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4+ microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together, these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.
Insights
Microglia diversity in Alzheimer's disease (AD) is key. Researchers found distinct microglial subtypes, including amyloid plaque-associated (XO4+) and non-associated (XO4-) cells, revealing unique molecular signatures and functions in AD pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia play a critical role in Alzheimer's disease (AD), but their diverse functions and molecular profiles are not fully understood.
- Existing research highlights the involvement of microglia in AD pathogenesis, yet specific subtypes and their contributions remain elusive.
Purpose of the Study:
- To investigate the molecular and functional diversity of microglia in an Alzheimer's disease mouse model.
- To identify distinct microglial populations based on amyloid plaque association and characterize their transcriptomic profiles.
- To explore the relevance of identified microglial signatures in human AD brains.
Main Methods:
- Isolation of microglia from an AD mouse model, differentiating between amyloid plaque-containing (XO4+) and non-containing (XO4-) populations.
- Transcriptomic analysis (RNA sequencing) to compare gene expression patterns between different microglial subtypes and aging/AD conditions.
- In vitro experiments using primary human microglia and BV2 mouse microglial cells to investigate the role of HIF1α in synaptosome phagocytosis.
Main Results:
- Distinct transcriptional trajectories were identified in aging and AD mice, with XO4+ microglia showing dysregulated gene expression linked to late-onset AD.
- A subset of human microglia from AD brains exhibited transcriptional programs similar to mouse XO4+ microglia.
- XO4- microglia displayed signatures of accelerated aging and accumulated more intracellular post-synaptic material, despite reduced phagocytosis, with HIF1α implicated in regulating this process.
Conclusions:
- This study reveals significant molecular and functional heterogeneity within microglia in the context of Alzheimer's disease.
- Findings highlight specific microglial subtypes (XO4+ and XO4-) with distinct transcriptomic profiles and roles in AD pathology and aging.
- The identification of HIF1α as a potential regulator of synaptosome phagocytosis offers new insights into microglial function in AD.
