Microglia Biology in Neurodegenerative Disease Models

Microglia, the resident immune cells of the central nervous system, play multifaceted roles in development, homeostasis, defence and repair. In models of neurodegenerative disease, these cells can adopt diverse functional states ranging from homeostatic surveillance to pro-inflammatory or phagocytic phenotypes. Their activation is shaped by local environmental cues—such as protein aggregates, myelin debris or neuronal injury—and is governed by complex transcriptional programmes. In vitro platforms, including stem cell-derived microglia and co-culture systems, have illuminated signalling pathways that regulate microglial survival, migration, cytokine release and synaptic pruning. In vivo, chimeric and transgenic animal models have been instrumental in linking microglial gene variants to disease progression, revealing how age, genetics and metabolism intersect to drive microglia-mediated neurotoxicity or repair. Collectively, these approaches have expanded our understanding of microglial contributions to pathologies such as Alzheimer’s, Parkinson’s and leukodystrophies, highlighting both therapeutic opportunities and challenges in modulating microglial function.

Research from Nature Portfolio

Recent studies have established an in vitro platform in which human stem cell-derived microglia are exposed to substrates such as synaptosomes, myelin debris or amyloid-β fibrils to recapitulate the transcriptional diversity observed in patient brain tissue. These investigations identified a key transcription factor that drives a highly phagocytic, disease-associated signature, enabling controlled manipulation of microglial states in homeostatic and disease-relevant contexts. Parallel work comparing human and mouse microglia under toll-like receptor stimulation revealed species-specific metabolic reprogramming, with distinct patterns of glycolytic enzyme induction, underscoring the necessity of human-based models for translational immunometabolism research. Foundational atlas studies of aged human microglia have further defined an age-related gene programme enriched in neurodegenerative risk loci, linking microglial senescence to genetic susceptibility and highlighting targets for modulating age-associated dysfunction.

Microglia Biology in Neurodegenerative Disease Models publication trend

The graph below shows the total number of articles in microglia biology in neurodegenerative disease models across all publications each year (not limited to Nature Index journals).

Technical terms

Microglia: Innate immune cells resident in the central nervous system, responsible for surveillance, phagocytosis and modulation of neuroinflammation.

Induced pluripotent stem cells (iPSCs): Adult somatic cells reprogrammed to an embryonic-like state, capable of differentiating into microglia and other cell types in vitro.

Disease-associated microglia (DAM): A microglial activation state characterised by a specific gene signature enriched in neurodegenerative disease contexts.

Metabolic reprogramming: The alteration of cellular energy pathways, such as shifts between oxidative phosphorylation and glycolysis, during immune activation.

Forward programming: A differentiation strategy that uses enforced expression of lineage-defining transcription factors to convert pluripotent stem cells directly into microglia.

Chimeric mouse model: A model organism engrafted with human cells, enabling in vivo study of human microglial identity, integration and response to pathology.

References

1. Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro. Nature Immunology (2023).
2. Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction. Nature Communications (2023).
3. A transcriptomic atlas of aged human microglia. Nature Communications (2018).
4. An adapted protocol to derive microglia from stem cells and its application in the study of CSF1R-related disorders. Molecular Neurodegeneration (2024).
5. Forward programming human pluripotent stem cells into microglia. Trends in Cell Biology (2024).
6. Development and validation of a simplified method to generate human microglia from pluripotent stem cells. Molecular Neurodegeneration (2018).