The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D
Open accessAbstract
Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia, where they form lipid droplets (LDs). We show that glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATPs), and apolipoproteins are critical for glial LD formation. MCTs enable glia to secrete and neurons to absorb lactate, which is converted to pyruvate and acetyl-CoA in neurons. Lactate metabolites provide a substrate for synthesis of fatty acids, which are processed and transferred to glia by FATP and apolipoproteins. In the presence of high ROS, inhibiting lactate transfer or lowering FATP or apolipoprotein levels decreases glial LD accumulation in flies and in primary mouse glial-neuronal cultures. We show that human APOE can substitute for a fly glial apolipoprotein and that APOE4, an Alzheimer's disease susceptibility allele, is impaired in lipid transport and promotes neurodegeneration, providing insights into disease mechanisms.
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APOE4 impairs neuron-glia lipid metabolism.
“APOE4, the strongest genetic risk factor for LOAD, impairs neuron–glia lipid metabolism14,16”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [16]
Many LDs in iMGs are peroxidated, suggesting that ROS may also occur first and the peroxidized lipids are sequestered in LDs.
“However, many LDs in iMGs were also peroxidated (Extended Data Fig. 11b–e), suggesting that ROS may also occur first and the peroxidized lipids are sequestered in LDs16,42,52.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [16]
ApoE-mediated transport of lipids from neurons to glia is neuroprotective in flies and mammalian cells.
“ApoE-mediated transport of lipids from neurons to glia in flies61 and mammalian cells is neuroprotective62.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [61]
Substitution of fly glial apolipoprotein with human ApoE4 is associated with reduced glial LD accumulation.
“a substitution of fly glial apolipoprotein with human ApoE4 is associated with reduced glial LD accumulation (Liu et al., 2017)”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Liu et al., 2017
ROS-stimulated microglial LD formation is mediated, in part, by apolipoproteins.
“Critically, ROS-stimulated microglial LD formation is mediated, in part, by apolipoproteins and transgenic human AD risk allele, ApoE-ε4, impairs LD formation a fly model [164].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [164]
Transgenic human AD risk allele ApoE-ε4 impairs LD formation in a fly model.
“Critically, ROS-stimulated microglial LD formation is mediated, in part, by apolipoproteins and transgenic human AD risk allele, ApoE-ε4, impairs LD formation a fly model [164].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [164]
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Characterization of two novel lipocalins expressed in the Drosophila embryonic nervous system
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The Science and Translation of Lactate Shuttle Theory
Brooks, G. A. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.008 · Cited by 1,486 · see citing works
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Lactate in the brain: from metabolic end-product to signalling molecule
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“This could involve LDAM as sequesters of excess ROS, which may prevent excessive inflammatory activation or limit ROS concentrations to protect against neuronal damage [164].”
BackgroundNeuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity
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Amyloid-β-independent regulators of tau pathology in Alzheimer disease
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ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism
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<i>APOE4</i> disrupts intracellular lipid homeostasis in human iPSC-derived glia
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Lipid droplets in the nervous system
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Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects
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Lipid-accumulated reactive astrocytes promote disease progression in epilepsy
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Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation
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Hepatocyte-Macrophage Acetoacetate Shuttle Protects Against Tissue Fibrosis
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APOE alters glucose flux through central carbon pathways in astrocytes
Williams, H. C., Farmer, B. C., Piron, M. A., Walsh, A. E., Bruntz, R. C., Gentry, M. S., Sun, R. C., & Johnson, L. A. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104742 · Cited by 105 · see citing works
The cell biology of APOE in the brain
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APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size
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Guo, J. L., Braun, D., Fitzgerald, G. A., Hsieh, Y.-T., Rougé, L., Litvinchuk, A., Steffek, M., Propson, N. E., Heffner, C. M., Discenza, C., et al. (2025) · Cell · doi:10.1016/j.cell.2024.10.027 · Cited by 91 · see citing works
“ApoE-mediated transport of lipids from neurons to glia in flies 61 and mammalian cells is neuroprotective.”
Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes
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PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia
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“Nonetheless, given that the APOE4 allele was recently found to induce LD accumulation in MGs and impair neuronal function 18,19 , our findings with PICALM further strengthen the notion of a causal role of LDs in mediating LOAD genetic risk factors, providing potential mechanistic targets for AD treatments.”
InfluentialSelf-citationProtective ApoE variants support neuronal function by effluxing oxidized phospholipids
Ralhan, I., Do, A. D., Bae, J.-Y., Feringa, F. M., Cai, W., Chang, J., Chik, K., Lee, N. Y. J., Gerry, C. J., van der Kant, R., et al. (2026) · Neuron · doi:10.1016/j.neuron.2025.10.040 · Cited by 23 · see citing works
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Protective ApoE variants support neuronal function by extracting peroxidated lipids
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Richards, S. E. V., Yang, M., Deik, A. A., & Ricq, E. L. (2025) · Neurochemical Research · doi:10.1007/s11064-025-04463-2 · Cited by 3 · see citing works
- Authors
- Liu, L., MacKenzie, K. R., Putluri, N., Maletić-Savatić, M., & Bellen, H. J.
- Affiliations
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bellen, Hugo J.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 26
- Issue
- 5
- Pages
- 719-737.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5677551
- OpenAlex
- W2760001608
- Cited by
- 556
- References
- 117
- Citations by year
- 2026: 54 · 2025: 103 · 2024: 78 · 2023: 77 · 2022: 63 · 2021: 66 · 2020: 53 · 2019: 32 · 2018: 26 · 2017: 3
- FWCI
- 15.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health & Human Development (1U54 HD083092)
- NIH (P30 AI036211, P30 CA125123, S10 RR024574, R01GM120033-01, 5R01GM067858)
- CPRIT Proteomics and Metabolomics Core Facility (RP120092)
- Dan L. Duncan Cancer Center
- Neuroscience Graduate Program Training (5T32GM008507-18)
- Rush and Helen Record Fellowship
- Robert A. and Renee E. Belfer Family Foundation
- Huffington Foundation
- Target ALS
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- reactive oxygen species, lipid droplets, monocarboxylate transporters, fatty acid transporters, apolipoprotein E, APOE ε4, Alzheimer's disease, lipogenesis, lactate metabolism, acetyl-CoA, lipid transport, neurodegeneration, Drosophila
- MeSH terms
- Animals, Astrocytes, Drosophila melanogaster, Female, Humans, Lipids, Male, Mice, Inbred C57BL, Neuroglia, Neurons, Reactive Oxygen Species, Coculture Techniques, Monocarboxylic Acid Transporters, Fatty Acid Transport Proteins, Mice, Apolipoprotein E4, Apolipoprotein E2, Apolipoproteins D, Primary Cell Culture, Lipid Droplets
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