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Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?
Yun Chen1,2, Marco Colonna1
1Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.
Abstract:
Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation of microglia. Because variants of genes expressed in microglia correlate with AD risk, microglial response to pathology plausibly impacts disease course. In mouse AD models, single-cell RNA sequencing (scRNA-seq) analyses delineated this response as progressive conversion of homeostatic microglia into disease-associated microglia (DAM); additional reactive microglial populations have been reported in other models of neurodegeneration and neuroinflammation. We review all of these microglial signatures, highlighting four fundamental patterns: DAM, IFN-microglia, MHC-II microglia, and proliferating microglia. We propose that all reported microglia populations are either just one or a combination, depending on the clustering strategy applied and the disease model. We further review single-nucleus RNA sequencing (snRNA-seq) data from human AD specimens and discuss reasons for parallels and discrepancies between human and mouse transcriptional profiles. Finally, we outline future directions for delineating the microglial impact in AD pathogenesis.
Insights
Microglia, the brain's immune cells, change in Alzheimer's disease (AD). This review identifies four key microglial patterns and discusses their relevance in human and mouse models.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) involves amyloid plaques, tau tangles, and neuronal loss.
- Microglia activation is a hallmark of AD pathology.
- Genetic risk factors for AD are linked to microglial gene expression.
Purpose of the Study:
- To review and categorize microglial responses in Alzheimer's disease models.
- To compare microglial signatures in mouse models with human AD data.
- To identify future research directions for understanding microglial roles in AD.
Main Methods:
- Review of single-cell RNA sequencing (scRNA-seq) data from mouse AD models.
- Analysis of single-nucleus RNA sequencing (snRNA-seq) data from human AD specimens.
- Comparative analysis of microglial transcriptional profiles across species and models.
Main Results:
- Four fundamental microglial patterns identified: disease-associated microglia (DAM), IFN-microglia, MHC-II microglia, and proliferating microglia.
- Proposed that diverse reported microglial populations represent variations or combinations of these four patterns.
- Highlighted parallels and discrepancies between mouse and human microglial transcriptional profiles in AD.
Conclusions:
- Microglial activation patterns are critical in Alzheimer's disease pathogenesis.
- Understanding these patterns is essential for developing effective AD therapies.
- Further research is needed to fully elucidate the role of microglia in human AD.
