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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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“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 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
“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
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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Sun, J., Gao, G., Wang, S., Li, S., Tang, J., Liu, H., & Tang, T.-S. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02776-4
“348 It will be valuable to explore how A β ‑ induced neuronal hyperactivity relates to lipid metabolism in astrocytes and microglia, and to assess shifts in AD risk genes (ApoE and TREM2) and synaptic markers (SNAP-25 and GFAP).”
Self-citationCuní-López, C., Root, J. T., Hao, Y., Blomberg, N., Koppes-den Hertog, S. J., Sacks, D., Trujillo, A. E., Ghirlando, R., Kowal, I., Epstein, J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-76565-6
“Various studies have shown that lipid droplets in fl uence intercellular communication 13,17,61 .”
ApoE4 impairs astrocyte lipid droplet formation via endolysosomal dysfunction
Ralhan, I., Bae, J.-Y., Lee, N. Y., Cai, W., Chang, J., Jarad, S., Gu, H., Zhang, D., & Ioannou, M. S. (2026) · doi:10.64898/2026.09.01.748585
Self-citation
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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