Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution
Hansruedi Mathys1, Chinnakkaruppan Adaikkan1, Fan Gao1
1Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract:
Microglia, the tissue-resident macrophages in the brain, are damage sensors that react to nearly any perturbation, including neurodegenerative diseases such as Alzheimer's disease (AD). Here, using single-cell RNA sequencing, we determined the transcriptome of more than 1,600 individual microglia cells isolated from the hippocampus of a mouse model of severe neurodegeneration with AD-like phenotypes and of control mice at multiple time points during progression of neurodegeneration. In this neurodegeneration model, we discovered two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively. Furthermore, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered disease stage-specific microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs.
Insights
Researchers identified two distinct types of reactive microglia in a mouse model of Alzheimer's disease (AD). This study reveals new insights into microglial heterogeneity and cellular reprogramming during neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Genomics
Background:
- Microglia are brain-resident immune cells that act as sensors for damage and disease.
- Neurodegenerative diseases, such as Alzheimer's disease (AD), trigger significant microglial responses.
- Understanding microglial heterogeneity is crucial for deciphering disease mechanisms.
Purpose of the Study:
- To investigate the molecular and cellular responses of microglia during neurodegeneration.
- To identify distinct reactive microglia phenotypes and their transcriptional programs.
- To characterize the heterogeneity and dynamic changes in microglia during AD progression.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was employed to analyze over 1,600 individual microglia cells.
- Microglia were isolated from the hippocampus of a severe neurodegeneration mouse model with AD-like phenotypes and control mice.
- Transcriptomic analysis was performed at multiple time points during neurodegeneration progression.
Main Results:
- Two distinct molecularly defined reactive microglia phenotypes were discovered, characterized by type I and type II interferon response genes.
- Significant heterogeneity in microglial responses to neurodegeneration was observed.
- Disease stage-specific microglia cell states and the trajectory of their cellular reprogramming were identified.
- Underlying transcriptional programs driving these microglial states were uncovered.
Conclusions:
- Microglial responses to neurodegeneration are highly heterogeneous and context-dependent.
- Distinct reactive microglia phenotypes, driven by interferon responses, emerge during AD-like pathology.
- This study provides a comprehensive map of microglial reprogramming and transcriptional dynamics in neurodegeneration.
