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Lipid Droplet-Accumulating Microglia as a Therapeutic Node in Neurodegenerative Disease
Siqi Guo1, Qingyu Zhang2, Rui Guo2
1Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Abstract:
Neurodegenerative disorders increasingly reflect failures of cellular state control rather than the linear accumulation of a single toxic lesion. Microglia become trapped in maladaptive states in which inflammatory activation is decoupled from effective cargo processing. Lipid droplet-accumulating microglia (LDAM) represent a recurrent convergence state across aging and neurodegeneration, characterized by persistent neutral lipid sequestration, reduced phagocytosis-to-degradation capacity, oxidative amplification, and chronic but functionally inefficient inflammation. LDAM emerges when lipid substrate influx exceeds the capacity of cholesterol efflux, lysosomal lipophagy, and mitochondrial β-oxidation, converting lipid droplets from transient buffers into stable metabolic anchors. This entrenchment is reinforced by mitochondrial exhaustion, vacuolar H+-ATPase-linked lysosomal deacidification, and inflammasome/interferon locking, often further amplified by cGAS-STING signaling. Together, these constraints converge on a state of metabolic-epigenetic locking that sustains permissive chromatin landscapes at pro-inflammatory loci. On this basis, state-resetting strategies are considered that rebalance lipid flux, restore organelle clearance capacity, and transiently restrain inflammatory amplification, while spatial multiomics and fluid biomarkers are discussed as candidate tools for stage- and niche-resolved stratification of combination interventions.
Insights
Microglia can become trapped in harmful inflammatory states, accumulating lipids and impairing function in neurodegenerative diseases. Resetting these cellular states may offer new therapeutic strategies for brain aging and disorders.
Area of Science:
- Neurobiology
- Cellular Biology
- Neuroimmunology
Background:
- Neurodegenerative disorders involve cellular state control failures, not just single lesions.
- Microglia adopt maladaptive inflammatory states, decoupling activation from cargo processing.
- Lipid droplet-accumulating microglia (LDAM) are a common state in aging and neurodegeneration.
Purpose of the Study:
- To characterize the mechanisms underlying the lipid droplet-accumulating microglia (LDAM) state.
- To explore how LDAM contributes to neuroinflammation and impaired cellular function.
- To identify potential state-resetting strategies for neurodegenerative disorders.
Main Methods:
- Analysis of lipid metabolism, organelle function, and inflammatory signaling in microglia.
- Investigating the role of lipid droplet accumulation, lysosomal function, and mitochondrial activity.
- Exploring epigenetic modifications and signaling pathways like cGAS-STING.
Main Results:
- LDAM state characterized by lipid sequestration, reduced phagocytosis, oxidative stress, and inefficient inflammation.
- LDAM emerges when lipid influx overwhelms clearance pathways (efflux, lipophagy, β-oxidation).
- Metabolic-epigenetic locking sustains pro-inflammatory gene expression in LDAM.
Conclusions:
- LDAM represents a metabolically and epigenetically entrenched state in neurodegeneration.
- Targeting lipid flux, organelle clearance, and inflammatory amplification are potential therapeutic avenues.
- Spatial multiomics and fluid biomarkers could aid in stratifying interventions for specific disease contexts.
