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Updated: Aug 20, 2025
Correlative Light and Electron Microscopy to Study Microglial Interactions with β-Amyloid Plaques
Published on: June 1, 2016
Plaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology
Jack I Wood1, Eugenia Wong2, Ridwaan Joghee2
1Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London WC1E 6BT, UK; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal Hospital, House V3, 43180 Mölndal, Sweden.
Abstract:
Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia-touching plaques, neighboring plaques, and far from plaques in an aged Alzheimer's mouse model with late plaque development. In 18-month-old APPNL-F/NL-F knockin mice, with and without the Alzheimer's disease risk mutation Trem2R47H/R47H, we report that expression of 38/55 PIGs have plaque-induced microglial upregulation, with a subset only upregulating in microglia directly contacting plaques. For seven PIGs, including Trem2, this upregulation is prevented in APPNL-F/NL-FTrem2R47H/R47H mice. These TREM2-dependent genes are all involved in phagocytic and degradative processes that we show correspond to a decrease in phagocytic markers and an increase in the density of small plaques in Trem2-mutated mice. Furthermore, despite the R47H mutation preventing increased Trem2 gene expression, TREM2 protein levels and microglial density are still marginally increased on plaques. Hence, both microglial contact with plaques and functioning TREM2 are necessary for microglia to respond appropriately to amyloid pathology.
Insights
Microglia respond to Alzheimer's plaques by altering gene expression, particularly when in direct contact. The TREM2 gene is crucial for this response, impacting microglial function and plaque development.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Alzheimer's disease (AD) is characterized by amyloid plaques.
- Microglia are the primary immune cells in the brain and play a role in AD pathogenesis.
- The TREM2 gene is implicated in microglial function and AD risk.
Purpose of the Study:
- To investigate plaque-induced gene (PIG) expression in microglia at different distances from amyloid plaques in an aged AD mouse model.
- To determine the role of the TREM2 R47H mutation in microglial response to plaques.
Main Methods:
- Spatial cell-type-enriched transcriptomics was used to analyze gene expression in microglia.
- APPNL-F/NL-F mice with and without the Trem2R47H/R47H mutation were studied.
- Plaque-induced gene expression was compared between microglia touching, neighboring, and distant plaques.
Main Results:
- Upregulation of 38/55 plaque-induced genes was observed in microglia, with some specific to plaque-contacting cells.
- TREM2-dependent upregulation of seven genes, including Trem2, was prevented in Trem2-mutated mice.
- TREM2-dependent genes are involved in phagocytosis and degradation, and their disruption led to decreased phagocytic markers and increased small plaque density.
- TREM2 protein and microglial density were marginally increased on plaques despite the R47H mutation hindering Trem2 gene expression.
Conclusions:
- Microglial contact with plaques and functional TREM2 are essential for appropriate microglial response to amyloid pathology.
- The TREM2 R47H mutation impairs TREM2-dependent microglial functions related to phagocytosis and plaque clearance.
- Understanding TREM2's role is critical for developing therapeutic strategies for Alzheimer's disease.
