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Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity
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Abstract
Metabolic coordination between neurons and astrocytes is critical for the health of the brain. However, neuron-astrocyte coupling of lipid metabolism, particularly in response to neural activity, remains largely uncharacterized. Here, we demonstrate that toxic fatty acids (FAs) produced in hyperactive neurons are transferred to astrocytic lipid droplets by ApoE-positive lipid particles. Astrocytes consume the FAs stored in lipid droplets via mitochondrial β-oxidation in response to neuronal activity and turn on a detoxification gene expression program. Our findings reveal that FA metabolism is coupled in neurons and astrocytes to protect neurons from FA toxicity during periods of enhanced activity. This coordinated mechanism for metabolizing FAs could underlie both homeostasis and a variety of disease states of the brain.
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“Reactive astrocytes can upregulate VLCFA-rich phosphatidylcholines, which drive the death of neurons and OLs, probably via lipoparticle secretion [415].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [415]
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“Injured neurons and oligodendrocytes have a low capacity for consuming FFAs and sequestering them into LDs61, making them more vulnerable to lipid-induced cytotoxicity in chronic inflammation62,63.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [63]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This neuron–astrocyte metabolic coupling, mediated by apoE, plays an essential role in preventing activity‐induced lipotoxicity in neurons. 1”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [1]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Ischemia is correlated with both increased lipid peroxidation and neutral lipid accumulation in the brain (Yoshida et al., 1982; Gasparovic et al., 2001; Ioannou et al., 2019).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Ioannou et al., 2019
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In the citing paper
“recent reports revealed a role of ApoE in transporting peroxidized FAs from neuron to astrocyte upon neuronal stimulation (Ioannou et al., 2019)”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Ioannou et al., 2019
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“Because LDL receptors are involved in neuron-to-astrocyte FA transfer (Ioannou et al., 2019), the lower ability of E4 astrocytes in uptaking LDL (Figure S3E) is consistent with a reduced capacity of E4 astrocytes in internalizing FAs.”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Ioannou et al., 2019
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“Strikingly, we observed substantial accumulation of LD-like lipid structures in neurons (Figure 1A; days in vitro 8 [DIV8]) under culture conditions without extra NMDA stimulation or oxidative challenge used previously (Ioannou et al., 2019).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Ioannou et al., 2019
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“while autophagy contributes to LD formation in NMDA-stimulated neurons (Ioannou et al., 2019)”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Ioannou et al., 2019
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“Upon oxidative stress or hyperactivity, neurons transfer peroxidized FAs to glia via ApoE-positive lipid particles (Ioannou et al., 2019).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Ioannou et al., 2019
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In the citing paper
“Other studies demonstrated that lipid peroxides formed in neurons under oxidative or excitotoxic stress can be transported by APOE-lipoproteins to astrocytes; astrocytes store these neuron-derived lipids in LDs, which protect against neurotoxicity and may play a role in detoxifying these deleterious lipid species (Walker et al., 2006; Liu et al., 2015, 2017; Ioannou et al., 2019; Moulton et al., 2”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Ioannou et al., 2019
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In the citing paper
“Other studies demonstrated that lipid peroxides formed in neurons under oxidative or excitotoxic stress can be transported by APOE-lipoproteins to astrocytes; astrocytes store these neuron-derived lipids in LDs, which protect against neurotoxicity and may play a role in detoxifying these deleterious lipid species (Walker et al., 2006; Liu et al., 2015, 2017; Ioannou et al., 2019; Moulton et al., 2”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Ioannou et al., 2019
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“Various studies have shown that lipid droplets influence intercellular communication13,17,61.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [61]
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In the citing paper
“In the brain, ApoE contributes to a bidirectional metabolic network that couples astrocytes and neurons (Ioannou et al., 2019;Liu et al., 2017;Qi et al., 2021).”
From Isoform- and cell-state-specific lipidation of ApoE in astrocytes (2022) · cites this paper as Ioannou et al., 2019
In the citing paper
“cell culture models have demonstrated that hyperactive neurons can release APOE-associated fatty acids which are taken up by astrocytes and buffer lipotoxic stress35.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [35]
In the citing paper
“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 [62]
In the citing paper
“In the CNS, apoE facilitates the transport of cholesterol and FAs between cells, maintaining lipid homeostasis.”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [1]
In the citing paper
“Astrocytes are critical for maintaining central nervous system (CNS) homeostasis, playing essential roles in lipid metabolism and the clearance of toxic protein aggregates.”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [1]
In the citing paper
“Collectively, these genes have been implicated in the coordination of lipid and oxidative metabolism between neurons and astrocytes30.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [30]
In the citing paper
“these results and those of others demonstrate that astrocytes and microglia secrete and degrade a huge array and quantity of lipids”
From Neurotoxic reactive astrocytes induce cell death via saturated lipids (2021) · cites this paper as [21]
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“5 Here we provide experimental evidence that in response to insulin, astrocytes shift their metabolic preference to fatty acids.”
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Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes
Tian, X., Rivera, E. K., Hwang, I., Nikitina, A. A., Smith, J. A., Cho, Y. J., Sala‐Jarque, J., DuBose, A., Andriola, C., Gollan‐Myers, T., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70589 · Cited by 7
Dembitskaya, Y., & Popov, A. (2025) · Metabolic Brain Disease · doi:10.1007/s11011-025-01706-7 · Cited by 8
“In response to metabolic stress or excess fatty acid supply, astrocytes can accumulate neutral lipids in cytoplasmic lipid droplets, which serve as temporary storage or buffers against lipotoxicity (Ioannou et al. 2019 ; TCW et al. 2022).”
Scale-spanning crosstalk between metabolism and information processing
Barros, L. F., Fernández‐Moncada, I., Marsicano, G., Ruminot, I., Saab, A. S., & Weber, B. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.10.012 · Cited by 8
Lipid metabolism and neurodegeneration: Mechanistic insights and therapeutic targets
Salas, Y. M., Kemper, K. M., Shanmughapriya, S., Langford, D., & Natarajaseenivasan, K. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103114 · Cited by 8
Zhu, X.-L., Zhang, H., Peng, W., Gao, S., Yang, Z., Zhang, J., & Liu, X. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.12.067 · Cited by 7
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CCDC50 mediates the clearance of protein aggregates to prevent cellular proteotoxicity
Ye, Y., Jia, P., Miao, J., Wang, Y., Li, Z., Lin, Y., He, M., Liu, S., Zheng, B., Wu, J., et al. (2024) · Autophagy · doi:10.1080/15548627.2024.2367183 · Cited by 7
“Lipid droplets are frequently detected in cultured cells and can be enhanced by proteotoxic stresses and autophagy defects [25].”
Ferrer, R. M., Jaspers, Y. R. J., Dijkstra, I. M. E., Breeuwsma, N., van Klinken, J. B., Romero, C., Engelen, M., Kemp, S., & Heine, V. M. (2024) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12832 · Cited by 7
“21 The efficient catabolic machinery within astrocytes is essential for processing these lipids and maintaining neuronal support.”
Sheng, J., Zhang, X., Liang, W., Lyu, J., Zhang, B., Min, J., Xu, A., Xu, X., Li, J. W., Li, J., et al. (2025) · BMC Biology · doi:10.1186/s12915-025-02175-1 · Cited by 6
“In most cases, the over-produced lipid in neurons can be further transported to the glia with the help of mono - carboxylate transporters (MCTs), fatty acid transport proteins (FATPs), and apolipoproteins (APOE) [64–66].”
Huang, X., Jiang, R., Xu, X., Zu, Q., Wu, F., Liu, S., & Shi, H. (2021) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.27407 · Cited by 7
“(Maokang Biotechnology, Shanghai, China) according to the manufacturer’s protocol.(28) Briefly, astrocytes were seeded in 24-well plates (Corning, NY) and exposed to experimental conditions.”
MethodCabezas, R., Martín-Jiménez, C., Zuluaga, M., Pinzón, A. M., Barreto, G. E., & González, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052474 · Cited by 8
“In this aspect, previous studies have shown that astrocytic lipid droplets have neuroprotective functions against lipotoxicity through mitochondrial β-oxidation in response to neuronal activity creating a detoxification \environment in a Sprague Dawley rat model [44].”
BackgroundJäntti, M. H., Jackson, S. N., Kuhn, J. F., Parkkinen, I., Sree, S., Hinkle, J. J., Jokitalo, E., Deterding, L. J., & Harvey, B. K. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2022.159219 · Cited by 7
Glial lipid droplets resolve ROS during sleep
Goodman, L. D., Moulton, M. J., & Bellen, H. J. (2024) · Nature Neuroscience · doi:10.1038/s41593-023-01546-7 · Cited by 7
Hexokinase and Glycolysis: Between Brain Cells Life and Death
da Mata, L. R. S., Santos, L., & César, M. C. (2023) · Current Chemical Biology · doi:10.2174/2212796817666230510095530 · Cited by 7
In the Brain, It Is Not All about Sugar
Antunes, B. C., Mateus, T., & Morais, V. A. (2024) · NeuroSci · doi:10.3390/neurosci5020016 · Cited by 6
“Astrocytes, for instance, have been shown to be quite flexible in the substrates used, with competences at the level of glycolysis and FAO [35,60].”
BackgroundShaw, A., Teng, R., Fasina, T., Gonzales, A.-S., Wong, A., Schweitzer, D. R., & Akefe, I. O. (2025) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2025.111299 · Cited by 6
“This coupling mechanism is likely to provide a protective mechanism for neurons from FA toxicity over periods of enhanced activity (Ioannou et al., 2019).”
Baek, G. H., Kim, D., Son, G., Do, H., Yeon, G., Lee, M. J., Ji, M., Son, J.-H., Ju, M., Ahn, I., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03176-w · Cited by 9
Molecular mechanisms underlying obesity-induced memory dysfunction: a comprehensive narrative review
Golkar, A., Razazpour, F., Dalfardi, M., & Baghcheghi, Y. (2025) · Physiology & Behavior · doi:10.1016/j.physbeh.2025.115119 · Cited by 7
Mitochondrial ROS sources steer neuroinflammation
Pan, H., & Yin, F. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01391-x · Cited by 6
Fat for thought: Lipid regulation of neural stem cell fate
Cabot, J., Santillan, A. J., Fernández‐García, P., Lladó, V., Torres, M., Escribá, P. V., & Castroflorio, E. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118785 · Cited by 7
Zou, P., Huang, Z., Zhang, Y., Zong, X., & Zhang, Q. (2026) · NeuroMolecular Medicine · doi:10.1007/s12017-026-08905-0 · Cited by 8
“This coupling prevents neuro - nal fatty acid accumulation and protects against lipotoxic - ity (Ioannou et al., 2019 ).”
Glucosylceramide-induced ectosomes propagate pathogenic α-synuclein in Parkinson’s disease
Jacquemyn, J., Marriott, B. A., Chang, J., Iftikhar, E., Chik, K., Lee, N. Y. J., Rubio-Atonal, L. F., Green, C., Wong, J., Acevedo-Morantes, C., et al. (2026) · Nature Cell Biology · doi:10.1038/s41556-026-01871-6 · Cited by 6
Self-citationAPOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons
Halim, D. O., Biase, E. D., Rajon, A., Jordi, L., Hallett, P. J., & Ole Isacson, A. (2026) · PNAS Nexus · doi:10.1093/pnasnexus/pgag053 · Cited by 7
“In the brain, however, high-density lipoprotein (HDL)-like particles containing APOE are produced locally, primarily by astrocytes, and, under certain conditions, by microglia (9, 10 ).”
Yao, Z., Godje, I. S. G., Jiao, B., Shen, L., & Luo, S. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103153 · Cited by 6
Cytosolic lipolysis in non‐adipose tissues: energy provision and beyond
Chen, S., & Huang, X. (2021) · FEBS Journal · doi:10.1111/febs.16161 · Cited by 8
Natarajaseenivasan, K., Garcia, A., Velusamy, P., Shanmughapriya, S., & Langford, D. (2022) · iScience · doi:10.1016/j.isci.2022.105407 · Cited by 7
Fatty acid preference for beta‐oxidation in mitochondria of murine cultured astrocytes
Corales, L. G., Inada, H., Owada, Y., & Osumi, N. (2024) · Genes to Cells · doi:10.1111/gtc.13144 · Cited by 6
The synaptic vesicle protein Mover/ TPRG1L is associated with lipid droplets in astrocytes
Krohn, J., Domart, F., Do, T. T., & Dresbach, T. (2023) · Glia · doi:10.1002/glia.24452 · Cited by 8
“This is especially important, because astrocytes also take up toxic lipid species released from neurons to protect them from lipotoxicity (Ioannou et al. 2019).”
BackgroundRopri, A. S., Lam, T. G., Kalia, V., Buchanan, H. M., Bartosch, A. M. W., Youth, E. H. H., Xiao, H., Ross, S. K., Jain, A., Chakrabarty, J. K., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14194 · Cited by 6
“46,47 Lipoicacidisan antioxidant and cofactor for several metabolic enzymes, and similarly to fatty acid oxidation, is linked to the generation of acetyl-CoA, 48,49 suggesting that there may be alterations in oxidative metabolism across multiple pathways as β -amyloid accumulates in the brain.”
BackgroundCRISPRi-based screens in iAssembloids to elucidate neuron-glia interactionsPreprint
Li, E., Benitez, C., Boggess, S. C., Koontz, M., Rose, I. V. L., Martinez, D., Dräger, N. M., Teter, O. M., Samelson, A. J., Pierce, N., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.26.538498 · Cited by 6
Comparative gene regulatory networks modulating APOE expression in microglia and astrocytesPreprint
Brase, L., Yu, Y., McDade, E., Dominantly Inherited Alzheimer Network (DIAN), Harari, O., & Benítez, B. A. (2024) · medRxiv · doi:10.1101/2024.04.19.24306098 · Cited by 6
“Neuronal activity produces reactive oxygen species (ROS), so these hyperactive neurons produce increased quantities of ROS which then peroxidate the fatty acids (pFA) found in the cell and organelle membranes 68 .”
Histamine synthesis and transport are coupled in axon terminals via a dual quality control system
Peng, L., & Wang, T. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00223-0 · Cited by 5
“EV1A) (Han et al, 2022; Ioannou et al, 2019).”
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Carnicero-Senabre, D., Barata, M. A., Jiménez-Villegas, J., Almeida, C. G., Cuadrado, A., & Rojo, A. I. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103853 · Cited by 5
“For instance, upon oxidative stress, peroxidized fatty acids are transported from neurons to astrocytes, via an ApoE-dependent mechanism to form lipid droplets and prevent neurodegeneration [75,76].”
Fueling the Mind: Brain Metabolism in Health and Neurodevelopmental Disorders
Marano, D., Mariano, V., & Novarino, G. (2025) · Annual Review of Genetics · doi:10.1146/annurev-genet-111523-102424 · Cited by 6
Astrocyte-Neuron Metabolic Synergies in Neurological Homeostasis and Disease
Dong, J., Gao, Z., Liu, M., Qian, B., Yuan, C., Liu, H., Rao, N., & Liu, Y. (2025) · Neurochemical Research · doi:10.1007/s11064-025-04548-y · Cited by 5
“This metabolic divergence underlies a unique neuro - protective mechanism: astrocytes uptake neuronal FAs via apolipoprotein E (ApoE) and sequester them in LDs [65, 77 ].”
Self-citationGlutamate decreases oxidative stress and lipid droplet formation in astrocytes
Rubio-Atonal, L. F., Chang, J., Jacquemyn, J., Ralhan, I., Ilarraza, I., & Ioannou, M. S. (2025) · Journal of Cell Science · doi:10.1242/jcs.263983 · Cited by 7
“…of magnitude depending on the compartment and/or biological context (Dzubay and Jahr, 1999; Kalivas, 2011), 100 µM glutamate was used, as this concentration was previously shown to increase lipid transport from neurons to astrocytes and reduce astrocyte lipid droplets (Ioannou et al., 2019a).”
InfluentialSelf-citationLiang, A., Zhang, L., Peng, J., Li, Y., Zhou, Y., Yang, C., Wang, J., Yan, Y., Mei, H., Zhu, J., et al. (2025) · Aging Cell · doi:10.1111/acel.70259 · Cited by 5
“…observed an abnormal accumulation of LDs in neurons co-cultured with senescent microglia (data not shown), despite prior evidence indicating that neurons possess limited capacity for intrinsic LD synthesis and typically offload excess lipids to astrocytes for detoxification (Ioannou et al. 2019).”
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“NFTs represent hallmark pathological alterations in cortical neurons of AD patients, directly contributing to neurite degeneration and serving as robust biomarkers of accelerated brain aging [8].”
Neuron–Glia Crosstalk in the Regulation of Astrocytic Antioxidative Mechanisms Following CNS Injury
Zakrzewski, P. K., & Boczek, T. (2025) · Antioxidants · doi:10.3390/antiox14121415 · Cited by 10
“On the other hand, it was confirmed that free fatty acids produced in the degradation of neuronal mitochondria can be transferred in ApoE+ (apolipoprotein E) lipid complexes to astrocytes, where the astrocyte mitochondrial β -oxidation pathway metabolizes them [83] (Figure 3).”
Ollen‐Bittle, N., Wang, W., Bean, K. M., Zhao, S., Buzatto, A. Z., Dong, Y., Li, L., & Whitehead, S. N. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70309 · Cited by 6
“They are essential components of cell membranes and axonal sheaths and take part in a vast range of requisite cellular processes in the brain including cell differentiation, energy storage, metabolism, and cell signaling (Ioannou et al. 2019; Bazan 2005; Montani 2021; Bansal et al. 1999).”
Astrocytic and microglial cell functions in neuroinflammatory diseases and their animal models
Hashimoto, K., Gotoh, M., & Ikeshima‐Kataoka, H. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1708775 · Cited by 8
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Sun, F., She, R., Yang, T., Chen, B., Liao, Z., Liao, J., & Mei, Z. (2026) · Phytomedicine · doi:10.1016/j.phymed.2026.157928 · Cited by 5
Cellular mechanisms of brain lipid metabolism in health and disease
Petrelli, F., Gilardi, C., Igelbüscher, C. M., Panfilova, D., Rey, A., Paolicelli, R. C., & Knobloch, M. (2026) · Nature Cell Biology · doi:10.1038/s41556-026-01880-5 · Cited by 7
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Metadata
- Authors
- Ioannou, M. S., Jackson, J., Sheu, S.-H., Chang, C.-L., Weigel, A. V., Liu, H., Pasolli, H. A., Xu, C. S., Pang, S., Matthies, D., Hess, H. F., Lippincott-Schwartz, J., & Liu, Z.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Alberta (CA)
- Corresponding author
- Ioannou, Maria S.
- Liu, Zhe
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 177
- Issue
- 6
- Pages
- 1522-1535.e14
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2946373463
- Cited by
- 760
- References
- 72
- Citations by year
- 2026: 129 · 2025: 150 · 2024: 133 · 2023: 117 · 2022: 74 · 2021: 92 · 2020: 47 · 2019: 15
- FWCI
- 23.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- fatty acid toxicity, lipid droplets, apolipoprotein E, mitochondrial beta-oxidation, fatty acid metabolism, neuronal hyperactivity, astrocytes, lipid metabolism, neuroprotection
- MeSH terms
- Animals, Apolipoproteins E, Astrocytes, Brain, Fatty Acids, Homeostasis, Male, Mice, Inbred C57BL, Mitochondria, Neurons, Oxidation-Reduction, Rats, Sprague-Dawley, Mice, Knockout, Lipid Metabolism, Mice, Rats, Lipid Droplets
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