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Microglia-to-neuron signaling links APOE4 and inflammation to enhanced neuronal lipid metabolism and network activity
Ana P Verduzco Espinoza1, Na Na1, Loraine Campanati1
1Department of Neuroscience, The Scripps Research Institute, San Diego, CA 92037.
Abstract:
Microglia regulate neuronal circuit plasticity. Disrupting their homeostatic function has detrimental effects on neuronal circuit health. Neuroinflammation contributes to the onset and progression of neurodegenerative diseases, including Alzheimer's disease (AD), with several microglial activation genes linked to increased risk for these conditions. Inflammatory microglia alter neuronal excitability, inducing metabolic strain. Interestingly, expression of APOE4, the strongest genetic risk factor for AD, affects both microglial activation and neuronal excitability, highlighting the interplay between lipid metabolism, inflammation, and neuronal function. It remains unclear how microglial inflammatory state is conveyed to neurons to affect circuit function and whether APOE4 expression alters this intercellular communication. Here, we use a reductionist model of human iPSC-derived microglial and neuronal monocultures to dissect how the APOE genotype in each cell type independently contributes to microglial regulation of neuronal activity during inflammation. Conditioned media (CM) from LPS-stimulated microglia increased neuronal network activity, assessed by calcium imaging, with APOE4 microglial CM driving greater neuronal activity than APOE3 CM. Both APOE3 and APOE4 neurons increase network activity in response to CM treatments, while APOE4 neurons uniquely increase presynaptic puncta in response to APOE4 microglial CM. CM-derived exosomes from LPS-stimulated microglia can mediate increases to network activity. Finally, increased network activity is accompanied by increased lipid droplet (LD) metabolism, and blocking LD metabolism abolishes network activity. These findings illuminate how microglia-to-neuron communication drives inflammation-induced changes in neuronal circuit function, demonstrate a role for neuronal LDs in network activity, and support a potential mechanism through which APOE4 increases neuronal excitability.
Insights
Inflammatory microglia, particularly those with APOE4, increase neuronal activity. This communication involves lipid metabolism and affects neuronal excitability, a key factor in Alzheimer's disease progression.
Area of Science:
- Neuroscience
- Neuroinflammation
- Genetics
Background:
- Microglia are crucial for neuronal circuit plasticity; their dysfunction contributes to neurodegenerative diseases like Alzheimer's disease (AD).
- Neuroinflammation, exacerbated by microglial activation, alters neuronal function and metabolism.
- APOE4, a major genetic risk factor for AD, influences both microglial and neuronal activity, suggesting a link between lipid metabolism, inflammation, and neuronal excitability.
Purpose of the Study:
- To investigate how microglial inflammatory states affect neuronal circuit function.
- To determine if APOE4 genotype influences microglia-neuron communication during inflammation.
- To elucidate the role of lipid metabolism in inflammation-induced neuronal activity.
Main Methods:
- Utilized human induced pluripotent stem cell (iPSC)-derived microglial and neuronal monocultures.
- Assessed neuronal network activity using calcium imaging.
- Analyzed conditioned media (CM) and exosomes from lipopolysaccharide (LPS)-stimulated microglia.
Main Results:
- LPS-stimulated microglia CM increased neuronal network activity, with APOE4 microglial CM showing a greater effect than APOE3.
- Both APOE3 and APOE4 neurons responded to CM, but APOE4 neurons showed increased presynaptic puncta with APOE4 microglial CM.
- Exosomes from activated microglia mediated increased network activity, which correlated with increased lipid droplet (LD) metabolism.
Conclusions:
- Microglia-to-neuron communication drives inflammation-induced changes in neuronal circuit function.
- Neuronal lipid droplets play a role in regulating network activity.
- APOE4 may increase neuronal excitability through altered microglia-neuron communication and lipid metabolism.
