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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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“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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“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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Citations
Cites
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400
Cutadapt removes adapter sequences from high-throughput sequencing reads
Martin, M. (2011) · EMBnet.journal · doi:10.14806/ej.17.1.200 · Cited by 33,889
RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome
Li, B., & Dewey, C. N. (2011) · BMC Bioinformatics · doi:10.1186/1471-2105-12-323 · Cited by 22,179
Trapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556
Trapnell, C., Roberts, A., Goff, L. A., Pertea, G. M., Kim, D., Kelley, D. R., Pimentel, H., Salzberg, S. L., Rinn, J. L., & Pachter, L. S. (2012) · Nature Protocols · doi:10.1038/nprot.2012.016 · Cited by 12,145
TopHat: discovering splice junctions with RNA-Seq
Trapnell, C., Pachter, L. S., & Salzberg, S. L. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp120 · Cited by 11,682
Shedding light on the cell biology of extracellular vesicles
van Niel, G., D'Angelo, G., & Raposo, G. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.125 · Cited by 8,369
Ayala, A., Muñoz, M., & Argüelles, S. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/360438 · Cited by 6,837
A guided tour into subcellular colocalization analysis in light microscopy
Bolte, S., & Cordelières, F. P. (2006) · Journal of Microscopy · doi:10.1111/j.1365-2818.2006.01706.x · Cited by 5,462
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875
Flagged first, then by citations
3 of the 72 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Reactive astrocyte nomenclature, definitions, and future directions
Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00783-4 · Cited by 2,513
Zhou, Y., Song, W. M., Andhey, P. S., Swain, A., Levy, T., Miller, K. R., Poliani, P. L., Cominelli, M., Grover, S., Gilfillan, S., et al. (2020) · Nature Medicine · doi:10.1038/s41591-019-0695-9 · Cited by 1,150
Lipid droplet biogenesis and functions in health and disease
Zadoorian, A., Du, X., & Yang, H. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00845-0 · Cited by 617
Neurotoxic reactive astrocytes induce cell death via saturated lipids
Guttenplan, K. A., Weigel, M. K., Prakash, P., Wijewardhane, P. R., Hasel, P., Rufen-Blanchette, U., Münch, A. E., Blum, J. A., Fine, J., Neal, M. C., et al. (2021) · Nature · doi:10.1038/s41586-021-03960-y · Cited by 578
APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia
Haney, M. S., Pálovics, R., Munson, C. N., Long, C., Johansson, P. K., Yip, O., Dong, W., Rawat, E., West, E., Schlachetzki, J. C. M., et al. (2024) · Nature · doi:10.1038/s41586-024-07185-7 · Cited by 536
“For example, cell culture models have demonstrated that hyperactive neurons can release APOE -associated fatty acids which are taken up by astrocytes and buffer lipotoxic stress 35 .”
Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity
Yoon, H., Shaw, J. L., Haigis, M. C., & Greka, A. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.027 · Cited by 538
Yin, F. (2023) · The FEBS Journal · doi:10.1111/febs.16344 · Cited by 441
Microglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases
Bartels, T., De Schepper, S., & Hong, S. (2020) · Science · doi:10.1126/science.abb8587 · Cited by 412
Energy metabolism in health and diseases
Liu, H., Wang, S., Wang, J., Guo, X., Song, Y., Fu, K., Gao, Z., Liu, D., He, W., & Yang, L. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02141-x · Cited by 484
Self-citationImmune cell regulation of glia during CNS injury and disease
Greenhalgh, A. D., David, S., & Bennett, F. C. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0263-9 · Cited by 411
Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism
Poitelon, Y., Kopec, A. M., & Belin, S. (2020) · Cells · doi:10.3390/cells9040812 · Cited by 394
“A recent study found that fatty acids are released by hyperactive neurons and can be taken up by neighboring glia to protect neurons from fatty acid toxicity [158].”
BackgroundApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism
Qi, G., Mi, Y., Shi, X., Gu, H., Brinton, R. D., & Yin, F. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108572 · Cited by 379
“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.”
BackgroundResultInfluentialLipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity
Victor, M. B., Leary, N., Luna, X., Meharena, H. S., Scannail, A. N., Bozzelli, P. L., Samaan, G., Murdock, M. H., von Maydell, D., Effenberger, A. H., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.07.005 · Cited by 316
Lipid metabolism and lipid signals in aging and longevity
Mutlu, A. S., Duffy, J., & Wang, M. C. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.03.034 · Cited by 326
Apolipoprotein E in lipid metabolism and neurodegenerative disease
Yang, L. G., March, Z. M., Stephenson, R. A., & Narayan, P. S. (2023) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2023.05.002 · Cited by 286
Lipid droplets and cellular lipid flux
Mathiowetz, A. J., & Olzmann, J. A. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01364-4 · Cited by 305
Lipid droplets in the nervous system
Ralhan, I., Chang, C.-L., Lippincott-Schwartz, J., & Ioannou, M. S. (2021) · Journal of Cell Biology · doi:10.1083/jcb.202102136 · Cited by 281
Self-citationFernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278
Lipid droplets in neurodegenerative disorders
Farmer, B. C., Walsh, A. E., Kluemper, J. C., & Johnson, L. A. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00742 · Cited by 270
Andersen, J. V., Schousboe, A., & Verkhratsky, A. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102331 · Cited by 263
iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer
Park, D. S., Kozaki, T., Tiwari, S. K., Moreira, M., Khalilnezhad, A., Torta, F., Olivié, N., Thiam, C. H., Liani, O., Silvin, A., et al. (2023) · Nature · doi:10.1038/s41586-023-06713-1 · Cited by 239
Strategies to reduce the risks of mRNA drug and vaccine toxicity
Bitounis, D., Jacquinet, E., Rogers, M. A., & Amiji, M. M. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00859-3 · Cited by 242
“can be pathogenic unless the peroxidized products are metabolically managed 153 .”
Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects
Feringa, F. M., & van der Kant, R. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.690372 · Cited by 226
Lipid-accumulated reactive astrocytes promote disease progression in epilepsy
Chen, Z.-P., Wang, S., Zhao, X., Fang, W., Wang, Z., Ye, H., Wang, M.-J., Ke, L., Huang, T., Lv, P., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01288-6 · Cited by 214
The “Neuro-Glial-Vascular” Unit: The Role of Glia in Neurovascular Unit Formation and Dysfunction
Kugler, E., Greenwood, J., & MacDonald, R. B. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.732820 · Cited by 228
Early Alzheimer’s disease pathology in human cortex involves transient cell states
Gazestani, V., Kamath, T., Nadaf, N. M., Dougalis, A., Burris, S. J., Rooney, B., Junkkari, A., Vanderburg, C., Pelkonen, A., Gomez-Budia, M., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.005 · Cited by 209
Ni, X.-C., Wang, H.-F., Cai, Y.-Y., Yang, D., Alolga, R. N., Liu, B., Li, J., & Huang, F.-Q. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102363 · Cited by 208
Rose, J., Brian, C., Pappa, A., Panayiotidis, M. I., & Franco, R. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.536682 · Cited by 196
Mitochondrial heterogeneity and homeostasis through the lens of a neuron
Pekkurnaz, G., & Wang, X. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00594-w · Cited by 201
Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition
Morant-Ferrando, B., Jiménez-Blasco, D., Alonso-Batan, P., Agulla, J., Lapresa, R., García-Rodríguez, D., Yunta-Sanchez, S., López-Fabuel, I., Fernández, E., Carmeliet, P., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00835-6 · Cited by 195
Lipid Metabolism Crosstalk in the Brain: Glia and Neurons
Barber, C. N., & Raben, D. M. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00212 · Cited by 188
The neuropathobiology of multiple sclerosis
Woo, M. S., Engler, J. B., & Friese, M. A. (2024) · Nature reviews. Neuroscience · doi:10.1038/s41583-024-00823-z · Cited by 205
“Suppression of the TCA might be regulated on a transcriptional level, which was demonstrated in an independent study that performed neuronal translatome profiling at a similar disease stage in EAE 104 .”
TREM2-dependent lipid droplet biogenesis in phagocytes is required for remyelination
Gouna, G., Klose, C., Bosch-Queralt, M., Liu, L., Gokce, O., Schifferer, M., Cantuti-Castelvetri, L., & Simons, M. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20210227 · Cited by 186
“For example, elevated reactive oxygen species induces the formation of lipid droplets, which sequester polyunsaturated fatty acids, protecting them from oxidative damage (Ioannou et al., 2019).”
BackgroundLipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases
Yang, D., Wang, X., Zhang, L., Fang, Y., Zheng, Q., Liu, X., Yu, W., Chen, S., Ying, J., & Hua, F. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00828-0 · Cited by 179
“Magistretti’s group evokes hippocampal neurons hyperactivity with N-methyl-D-aspartate (NMDA) and observed a significant increase in FAs transfer from neurons to astrocytes by ApoE-positive lipid particles [26].”
BackgroundA serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility
Sheu, S.-H., Upadhyayula, S., Dupuy, V., Pang, S., Deng, F., Wan, J., Walpita, D., Pasolli, H. A., Houser, J., Sanchez-Martinez, S., et al. (2022) · Cell · doi:10.1016/j.cell.2022.07.026 · Cited by 162
“Prior to the completion of this manuscript, these datasets have been shared with others to examine lipid droplets (Ioannou et al., 2019), myelin distribution along large axons (Gao et al., 2019), and mitochondrial morphology (Delgado et al., 2019).”
Self-citationMoulton, M. J., Barish, S., Ralhan, I., Chang, J., Goodman, L. D., Harland, J. G., Marcogliese, P. C., Johansson, J. O., Ioannou, M. S., & Bellen, H. J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2112095118 · Cited by 180
Self-citationAstrocyte-oligodendrocyte interaction regulates central nervous system regeneration
Molina-Gonzalez, I., Holloway, R. K., Jiwaji, Z., Dando, O., Kent, S. A., Emelianova, K., Lloyd, A. F., Forbes, L. H., Mahmood, A., Skripuletz, T., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39046-8 · Cited by 176
“Next, using a previously established in vitro method to track direct cholesteroltransferbetweencelltypes 37 ,weloadedastrocyteswiththe fl uorescent cholesterol analogue Bodipy-FL-C12 for 6h (Fig.”
Lipid droplets and polyunsaturated fatty acid trafficking: Balancing life and death
Danielli, M., Perne, L., Jarc Jovičić, E., & Petan, T. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1104725 · Cited by 180
“However, enhanced neuronal activity leads to the accumulation of FAs and to an increase in lipid peroxidation levels, and surprisingly, also to modest LD accumulation, indicating that excess FAs could be partially stored in neuronal LDs (Ioannou et al., 2019).”
BackgroundInfluentialFatty acid metabolism in the progression and resolution of CNS disorders
Bogie, J. F. J., Haidar, M., Kooij, G., & Hendriks, J. J. A. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.01.004 · Cited by 167
Microglia and lipids: how metabolism controls brain innate immunity
Chausse, B., Kakimoto, P. A., & Kann, O. (2021) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2020.08.001 · Cited by 181
Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK
Li, Y., Munoz-Mayorga, D., Nie, Y., Kang, N., Tao, Y., Lagerwall, J., Pernaci, C., Curtin, G., Coufal, N. G., Mertens, J., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.014 · Cited by 160
Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis
Chaves‐Filho, A. B., Pinto, I. F. D., Dantas, L. S., Xavier, A. M., Inague, A., de Faria, R. L., de Medeiros, M. H. G., Glezer, I., Yoshinaga, M. Y., & Miyamoto, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-48059-7 · Cited by 162
Sun, Y., Zhang, H., Zhang, X., Wang, W., Chen, Y., Cai, Z., Wang, Q., Wang, J., & Shi, Y. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102690 · Cited by 151
Andersen, J. V., & Schousboe, A. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15811 · Cited by 161
“During intense signaling activity, neurons release the lipoprotein APOE loaded with fatty acids, which is taken up and accumulated by astrocytes (Ioannou et al., 2019).”
BackgroundThe Glutamate/ GABA ‐Glutamine Cycle: Insights, Updates, and Advances
Andersen, J. V. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70029 · Cited by 170
“During intense neuronal signaling, neurons may transfer APOE particles loaded with fatty acids to astrocytes for subsequent metabolism (Ioannou et al. 2019).”
Insights into Alzheimer’s disease from single-cell genomic approaches
Murdock, M. H., & Tsai, L.-H. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01222-2 · Cited by 148
Lipid droplets and lipid mediators in viral infection and immunity
Monson, E. A., Trenerry, A. M., Laws, J., Mackenzie, J. M., & Helbig, K. J. (2020) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuaa066 · Cited by 145
“Neurons have also been demonstrated to secrete excess FAs, which are taken up by astrocytic LDs during times of enhanced activity (Ioannou et al. 2019).”
BackgroundPapsdorf, K., Miklas, J. W., Hosseini, A., Cabruja, M., Morrow, C. S., Savini, M., Yu, Y., Silva-García, C. G., Haseley, N. R., Murphy, L., et al. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01136-6 · Cited by 153
A neuron–glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis
Haynes, P. R., Pyfrom, E. S., Li, Y., Stein, C., Cuddapah, V. A., Jacobs, J. A., Yue, Z., & Sehgal, A. (2024) · Nature Neuroscience · doi:10.1038/s41593-023-01568-1 · Cited by 149
“Nevertheless, daily sleep is important for detoxifying ROS and/or preventing ROS generation, and we suggest that it occurs in a brain-wide fashion at least in part through the mechanisms that we report here.”
InfluentialKelly, W., Duque, A. E. D., Michalek, J. E., Konkel, B., Caflisch, L., Chen, Y., Pathuri, S. C., Madhusudanannair-Kunnuparampil, V., Floyd, J., & Brenner, A. J. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-2807 · Cited by 147
“It is hypothesized that native astrocytes shuttle and store free fatty acids as a way of decreasing lipotoxicity to neurons (16).”
BackgroundGlia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation
Silva, B., Mantha, O. L., Schor, J., Pascual, A., Plaçais, P.-Y., Pavlowsky, A., & Préat, T. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00528-6 · Cited by 145
Astrocytes in stress accumulate lipid droplets
Smolič, T., Tavčar, P., Horvat, A., Černe, U., Halužan Vasle, A., Tratnjek, L., Kreft, M. E., Scholz, N., Matis, M., Petan, T., et al. (2021) · Glia · doi:10.1002/glia.23978 · Cited by 127
“…E-like particles and stored in astroglial LDs, because astrocytes, in contrast to neurons, have the capacity to use FFAs in β-oxidation and fight the mitochondrial overproduction of ROS during β-oxidation (Bailey et al., 2015; Ioannou et al., 2019; L. Liu et al., 2017; L. Liu et al., 2015).”
BackgroundMethodInfluentialOligodendroglial fatty acid metabolism as a central nervous system energy reserve
Asadollahi, E., Trevisiol, A., Saab, A. S., Looser, Z. J., Dibaj, P., Ebrahimi, R., Kusch, K., Ruhwedel, T., Möbius, W., Jahn, O., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01749-6 · Cited by 130
“To also rule out the possibility that inhibition of β-oxidation interferes with degradation of toxic FAs generated in hyperactivated neurons 25 leading to the decline of CAPs, we compared optic nerve conduction in the presence of 10 mM glucose.”
MethodChen, M., Gao, Q., Ning, H., Chen, K., Gao, Y., Yu, M., Liu, C., Zhou, W., Pan, J., Wei, L., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.06.020 · Cited by 159
Lipidome atlas of the adult human brain
Osetrova, M., Tkachev, A., Mair, W., Larraz, P. G., Efimova, O., Kurochkin, I., Stekolshchikova, E., Anikanov, N. A., Foo, J. C., Cazenave‐Gassiot, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48734-y · Cited by 138
“Inadditionto these well-established roles, lipids are now recognized to critically contribute to brain energy metabolism 26 , cell type differentiation 27,28 , neuronal and glial signaling 28 – 30 , control of in fl ammatory response 31 and modulation of protein complexes 32 .”
Lipid droplet availability affects neural stem/progenitor cell metabolism and proliferation
Ramosaj, M., Madsen, S., Maillard, V., Scandella, V., Sudria-Lopez, D., Yuizumi, N., Telley, L., & Knobloch, M. (2021) · Nature Communications · doi:10.1038/s41467-021-27365-7 · Cited by 122
Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective
Mulica, P., Grünewald, A., & Pereira, S. L. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.668517 · Cited by 126
“Astrocyte-Neuron Fatty Acid Coupling Recently, an elegant mechanism coupling fatty acids (FA) metabolism in neurons and astrocytes was exposed (60).”
BackgroundJacquet, A. D. R., Alpaugh, M., Denis, H. L., Tancredi, J. L., Boutin, M. E., Decaestecker, J., Beauparlant, C., Herrmann, L., Saint‐Pierre, M., Parent, M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39038-8 · Cited by 126
“They engage in diverse roles, from metabolic coupling with neighboring cells 9 to functions typically associated with the innate immune system, including antigen presentation 10 and secretion of in fl ammatory mediators 11 .”
Lipid metabolism in astrocytic structure and function
Lee, J. A., Hall, B., Allsop, J., Alqarni, R., & Allen, S. P. (2021) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2020.07.017 · Cited by 116
Tong, B., Ba, Y., Li, Z., Yang, C., Su, K., Qi, H., Zhang, D., Liu, X., Wu, Y., Chen, Y., et al. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106505 · Cited by 117
“Toxic fatty acids (FAs) generated in hyperactive neurons are transported to astrocyte lipid droplets via APOE-positive lipid particles and consumed through mitochondrial beta-oxidation for detoxification (Ioannou et al., 2019).”
BackgroundBrekk, O. R., Honey, J. R., Lee, S., Hallett, P. J., & Ole Isacson, A. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2003021117 · Cited by 115
“How do these results relate to the pathophysiological conditions involving cellular lipid content and transfer? An elevated lipid load in PD SN dopaminergic neurons is correlated with reduced SN astrocytic lipid content, and export of lipid-bound apolipoproteins through the ER secretory pathway is required for the ini…”
InfluentialMetabolic changes favor the activity and heterogeneity of reactive astrocytes
Xiong, X., Tang, Y., & Yang, Q. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2022.03.001 · Cited by 110
“For example, evidence suggests that toxic fatty acids produced in hyperactive neurons are transferred to astrocytic LD to yield energy via mitochondrial β-oxidation [60], which may be partly related to the fact that FAO genes are expressedmore in astrocytes than in neurons [61].”
Protein Quality Control and Lipid Droplet Metabolism
Roberts, M. A., & Olzmann, J. A. (2020) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-031320-101827 · Cited by 112
“Neurons have a limited capacity to generate LDs, and recent findings demonstrate that these cells actively traffic damaged lipids via apolipoprotein E particles to astrocytes, which sequester these lipids in LDs prior to degradation (Ioannou et al. 2019, Liu et al. 2017a).”
BackgroundBrain energy metabolism: A roadmap for future research
Rae, C. D., Baur, J. A., Borges, K., Dienel, G. A., Díaz‐García, C. M., Douglass, S. R., Drew, K. L., Duarte, J. M. N., Durán, J., Kann, O., et al. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16032 · Cited by 113
Lipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson’s disease
Hallett, P. J., Engelender, S., & Ole Isacson, A. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1532-2 · Cited by 105
Han, X., Zhao, S., Song, H., Xu, T., Fang, Q., Hu, G., & Sun, L. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101911 · Cited by 107
Prakash, P., Manchanda, P., Paouri, E., Bisht, K., Sharma, K., Rajpoot, J., Wendt, V., Hossain, A., Wijewardhane, P. R., Randolph, C. E., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.029 · Cited by 104
Kaji, S., Berghoff, S. A., Spieth, L., Schlaphoff, L., Sasmita, A. O., Vitale, S., Büschgens, L., Kedia, S., Zirngibl, M., Nazarenko, T., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.09.014 · Cited by 104
The cell biology of APOE in the brain
Windham, I. A., & Cohen, S. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.09.004 · Cited by 103
Diversity of satellite glia in sympathetic and sensory ganglia
Mapps, A. A., Thomsen, M. B., Boehm, E. D., Zhao, H., Hattar, S. S., & Kuruvilla, R. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110328 · Cited by 107
Afridi, R., Kim, J., Rahman, M. H., & Suk, K. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00020 · Cited by 102
Focusing on mitochondria in the brain: from biology to therapeutics
Song, N., Mei, S., Wang, X.-X., Hu, G., & Lu, M. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00409-w · Cited by 111
“These transferred FAs flow into astrocytic mitochondria for detoxification [218].”
BackgroundAPOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size
Windham, I. A., Powers, A. E., Ragusa, J. V., Wallace, E. D., Zanellati, M. C., Williams, V. H., Wagner, C. H., White, K. K., & Cohen, S. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202305003 · Cited by 96
“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).”
BackgroundMitochondrial dysfunction in astrocytes: A role in Parkinson’s disease?
Bantle, C. M., Hirst, W. D., Weihofen, A., & Shlevkov, E. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.608026 · Cited by 95
“Mitochondrial depolarization translocates cardiolipin from the inner mitochondrial membrane (IMM) to the outer mitochondrial membrane (OMM) where it associates to NLRP3 (Iyer et al., 2013).”
BackgroundKim, O. Y., & Song, J. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122356 · Cited by 96
Lipid droplets and fatty acid‐induced lipotoxicity: in a nutshell
Obaseki, E., Adebayo, D., Bandyopadhyay, S., & Hariri, H. H. (2024) · FEBS Letters · doi:10.1002/1873-3468.14808 · Cited by 100
“Similarly, in the context of neural development from neural stem/progenitor cells (NSPCs), LD lipolysis via ATGL was found to be essential for NSPC proliferation [39].”
BackgroundGuo, 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
“62 Additionally, APOE4 expression in human iMg was shown to induce secretion of lipids, which promoted tau phosphorylation in neurons.”
Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency
Vos, M. H., Dulovic‐Mahlow, M., Mandik, F., Frese, L., Kanana, Y., Diaw, S. H., Depperschmidt, J., Böhm, C., Rohr, J., Lohnau, T., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2025347118 · Cited by 95
“A lack of lipid uptake by glia cells results in neurodegeneration (55, 56).”
BackgroundLipid Droplet–Mitochondria Contacts in Health and Disease
Fan, H., & Tan, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25136878 · Cited by 90
“The proximity of LDs to mitochondria minimizes the diffusion distance, allowing for the efficient transfer of fatty acids [70].”
BackgroundAndersen, J. V., Westi, E. W., Jakobsen, E., Urruticoechea, N., Borges, K., & Aldana, B. I. (2021) · Molecular Brain · doi:10.1186/s13041-021-00842-2 · Cited by 89
Jacquet, A. D. R., Tancredi, J. L., Lemire, A. L., DeSantis, M. C., Li, W., & O’Shea, E. K. (2021) · eLife · doi:10.7554/elife.73062 · Cited by 91
“, 2018), for trophic and metabolic support (Allen and Lyons, 2018), and detoxification of harmful factors (Ioannou et al., 2019).”
BackgroundAlarcón-Gil, J., Sierra‐Magro, A., Morales-Garcia, J. A., Sanz-SanCristóbal, M., Alonso‐Gil, S., Cortés‐Canteli, M., Niso‐Santano, M., Martínez-Chacón, G., Fuentes, J. M., Santos, Á., et al. (2022) · Cells · doi:10.3390/cells11152297 · Cited by 87
“Furthermore, this evidence may relate to recent research showing a lipid metabolic coupling between neurons and astrocytes [13,14], whose failure is related to the presence of Apolipoprotein E4 and its alterations (the principal risk factor for Alzheimer’s disease) [14,31].”
BackgroundApolipoprotein E4 and meningeal lymphatics in Alzheimer disease: a conceptual framework
Mentis, A. A., Dardiotis, E., & Chrousos, G. P. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0731-7 · Cited by 83
Apolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities
Belaidi, A. A., Bush, A. I., & Ayton, S. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00843-y · Cited by 91
“Co-culture studies of astrocytes and neurons further showed that apoE4 was less efficient in lipid clearance from neurons [51–53].”
Lipid metabolism, remodelling and intercellular transfer in the CNS
Vanherle, S., Loix, M., Miron, V. E., Hendriks, J. J. A., & Bogie, J. F. J. (2025) · Nature reviews. Neuroscience · doi:10.1038/s41583-025-00908-3 · Cited by 96
“A recent study showed that lipid fluxes between neurons and astrocytes are also essential for protection against the adverse effects of neuronal hyperactivity 159 , a hallmark of neurological disorders such as Alzheimer disease 160 .”
InfluentialIsoform- and cell-state-specific lipidation of ApoE in astrocytes
Lindner, K., Beckenbauer, K., van Ek, L. C., Titeca, K., de Leeuw, S. M., Awwad, K., Hanke, F., Korepanova, A. V., Rybin, V., van der Kam, E. L., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110435 · Cited by 84
Recent insights on astrocyte mechanisms in CNS homeostasis, pathology, and repair
Hart, C. G., & Karimi‐Abdolrezaee, S. (2021) · Journal of Neuroscience Research · doi:10.1002/jnr.24922 · Cited by 88
Neurogenetic basis for circadian regulation of metabolism by the hypothalamusPreprint
Cedernaes, J., Waldeck, N. J., & Bass, J. T. (2019) · Genes & Development · doi:10.1101/gad.328633.119 · Cited by 89
“…which is accompanied by increased availability of nutrients, promotes energy use in neurons, thereby resulting in greater production of waste products that reflect cellular metabolism and redox state, such as amyloid β and τ proteins (Bero et al. 2011; Macauley et al. 2015; Ioannou et al. 2019).”
BackgroundInfluentialHypothalamic inflammation in metabolic disorders and aging
Bhusal, A., Rahman, M. H., & Suk, K. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04019-x · Cited by 87
“Another study reported that neuron–astrocyte metabolic coupling protects neurons from fatty acid toxicity during excitatory conditions [336].”
BackgroundVelebit, J., Horvat, A., Smolič, T., Mihevc, S. P., Rogelj, B., Zorec, R., & Vardjan, N. (2020) · Scientific Reports · doi:10.1038/s41598-020-62864-5 · Cited by 82
Hunger-promoting AgRP neurons trigger an astrocyte-mediated feed-forward autoactivation loop in mice
Varela, L., Stutz, B., Song, J. E., Kim, J. G., Liu, Z.-W., Gao, X., & Horváth, T. L. (2021) · Journal of Clinical Investigation · doi:10.1172/jci144239 · Cited by 75
“Previous reports have described that in hippocampal and cortical areas, neurons communicate with adjacent astrocytes by releasing various neurotransmitters (29, 31–33).”
Self-citationNeuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice
Berghoff, S. A., Spieth, L., Sun, T., Hosang, L., Depp, C., Sasmita, A. O., Vasileva, M. H., Scholz, P., Zhao, Y., Krueger-Burg, D., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109889 · Cited by 76
Takahashi, S. (2020) · Neuropathology · doi:10.1111/neup.12639 · Cited by 77
Al‐Dalahmah, O., Argenziano, M., Kannan, A., Mahajan, A., Furnari, J. L., Paryani, F., Boyett, D. M., Save, A., Humala, N., Khan, F., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38186-1 · Cited by 75
“Astrocytes play key roles in lipid metabolism; for example, in synthesizing fatty acids necessary for neuronal membranes 33 and catabolizing fatty acids released by neurons during excitotoxicity 42 .”
Remembering your A, B, C's: Alzheimer's disease and ABCA1
Lewandowski, C. T., Laham, M. S., & Thatcher, G. R. J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.01.011 · Cited by 76
Nakajima, S., Gotoh, M., Fukasawa, K., Murakami‐Murofushi, K., & Kunugi, H. (2019) · Brain Research · doi:10.1016/j.brainres.2019.146484 · Cited by 72
Wang, Y., Fu, A. K. Y., & Ip, N. Y. (2021) · FEBS Journal · doi:10.1111/febs.15878 · Cited by 75
How the brain fights fatty acids’ toxicity
Schönfeld, P., & Reiser, G. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105050 · Cited by 71
Castellanos, D. B., Martín-Jiménez, C., Rojas-Rodríguez, F., Barreto, G. E., & González, J. (2021) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2021.100899 · Cited by 75
Girard, V., Jollivet, F., Knittelfelder, O. L., Celle, M., Arsac, J.-N., Chatelain, G., van den Brink, D. M., Baron, T., Shevchenko, A., Kühnlein, R. P., et al. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009921 · Cited by 70
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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