Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory
Open accessAbstract
Astrocytes metabolically interact with neighboring neurons by providing multiple substances to neurons. How astrocytes regulate neural functions via altering the neuronal metabolic state remains elusive. Here, we demonstrate that astrocytic ApoE vectors a variety of microRNAs (miRNAs), and these miRNAs specifically silence genes involved in neuronal cholesterol biosynthesis, ultimately accounting for accumulation of the pathway-initiating substrate acetyl-CoA. Consequently, histone acetylation is promoted, and transcription is activated in neurons. Functionally, we demonstrate that ApoE-mediated neuronal histone acetylation leads to increased H3K27ac enrichment in the promoters of multiple neuronal immediate early genes and subsequently to enhanced memory consolidation in mice. Importantly, human ApoE4 vectors lower levels of miRNAs than ApoE3 and therefore is less capable of metabolic and epigenetic regulation in neurons. Collectively, our findings define an astrocytic ApoE-mediated neuronal epigenetic mechanism as a novel means through which astrocytes modulate brain connectivity and function.
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sApoE has been found to influence the transcriptome by modulating histone acetylation.
“Of note, sApoE has been found to influence the transcriptome by modulating histone acetylation (68, 69).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [68]
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“Immunofluorescence Staining Immunofluorescence staining was performed as described previously (Li et al., 2021).”
MethodSelf-citationAstrocyte Lipid Droplet Dynamics Orchestrate Neurological Disorders and Therapeutic Horizons
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“Conversely, ApoE4 undermines astrocytic support for neurons, manifesting in mitochondrial dysfunction and impaired lipid metabolism in neurons, as well as the upregulation of proinflammatory genes in microglia (Preman et al. 2024; Li et al. 2021; Qi et al. 2021).”
Ferroptosis: A new strategy for targeting Alzheimer’s disease
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“Growing evidences suggest that astrocytes can release different active molecules, which alter neuronal metabolism and potentiate transcription and translation of neuronal plasticity-related genes (Yang et al., 2014; Descalzi et al., 2019; Li et al., 2021; Salmina et al., 2021).”
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“In terms of glia-neuron crosstalk, astrocytic apolipoprotein can transport miRNAs that silence pivotal enzymes involved in cholesterol synthesis and promote histone acetylation in neurons [35].”
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“31 Furthermore, Li Q et al. confirmation that microglia lipid droplet accumulation is associated with diabetes-related cognitive dysfunction.”
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“Though ApoE is mostly linked to cholesterol efflux and reverse cholesterol transport, it is reported that astrocytic ApoE vectors a variety of microRNAs (miRNAs) that specifically silence genes involved in neuronal cholesterol biosynthesis (Li et al., 2021).”
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“Moreover, specific knockdown of ApoE in hippocampal astrocytes induces notable learning and memory deficits [ 11 ].”
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“…of cholesterol in the cytoplasmic compartment (Miziorko, 2011) and protein acetylation in the nucleus (Wellen et al., 2009), downregulation of the cholesterol/mevalonate pathway might therefore enhance acetyl-CoA availability to increase histone acetylation as seen in the Li et al. (2021) study.”
InfluentialLiu, N., Yu, W., Sun, M., Zhou, D., Sun, J., Jiang, T., Zhang, W., & Wang, M. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e29418 · Cited by 10 · see citing works
Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical
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Self-citationAlzheimer's disease phenotype based upon the carrier status of the apolipoprotein E ɛ4 allele
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“Multiple microRNAs of astrocytes play a role in regulating CL synthesis in neurons by increasing histone acyl-coenzymes and stimulating CL metabolism [28].”
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“It also has been suggested that apoE lipoproteins may contain RNA species of astrocytic origin and those upon the lipoprotein internalization may regulate neuronal lipid metabolism (Li et al., 2021).”
BackgroundMicroRNAs on the move: microRNAs in astrocyte-derived ApoE particles regulate neuronal function
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Metabolism and metabolomics in senescence, aging, and age-related diseases: a multiscale perspective
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Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System
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“Of note, it has recently been reported that ApoE also transports miRNAs, which inhibit the expression of genes promoting cholesterol synthesis in neurons [32].”
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“This differentiation is known to be important [69, 70], and differences in the effects of neuronal ApoE and astrocytic ApoE on various systems have been thoroughly studied [68–71].”
BackgroundWhat's been hidden in hidden hearing loss.
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“We acknowledge the reviewer's concern regarding the use of the early-onset familial Alzheimer's disease mouse model (3xTg), which is indeed a significant limitation of our study.”
Emerging roles of astrocytes in hippocampal circuitry and behavior
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Lipid droplets in astrocytes: Key organelles for CNS homeostasis and disease (Review)
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“Research has iden‑ tified key cholesterol transporters, including APOE (63) and members of the ATP‑binding cassette transporter family, such as ATP‑binding cassette subfamily A member 1 (ABcA1) (64) and ABcG4 (65).”
Self-citationInvestigating the shared genetic architecture between frailty and insomnia
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“Animal experiments demonstrated that increased H3K27ac enrichment in early gene promoters of neurons enhances memory capacity in mice, thereby influencing aging (Li et al., 2021).”
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“The decreased cholesterol delivery by ApoE4 to the long and extensively arborized axons of the metabolically taxed cholinergic neurons requires them to expend energy on cholesterol synthesis and to consume acetyl coenzyme A (acetyl-CoA) [53].”
BackgroundSelf-citationMechanistic insights on non-coding RNAs in learning and memory.
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“Beyond Alzheimer-related phenotypes, new work shows that astrocytes can adjust neuronal cholesterol content through ApoE-dependent programs that rewire neuronal physiology [89–92].”
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Acylation of the Rat Brain Proteins is Affected by the Inhibition of Pyruvate Dehydrogenase in vivo
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“The studies of the brain protein acylation system indicate that memory formation and age- or disease-related memory impairment depend not only on the long-known histone acetylation [17, 49-51], but also on histone succinylation [12].”
BackgroundHMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer’s disease
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“Fer-1 quelled angiotensin-II-provoked inflammatory cascades and stellate-cell ferroptosis by dampening ROS surge and repressing Nrf2 together with GPX expression (Li et al., 2021a).”
ApoE maintains neuronal integrity via microRNA and H3K27me3-mediated repression
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- Authors
- Li, X., Zhang, J., Li, D., He, C., He, K., Xue, T., Wan, L., Zhang, C., & Liu, Q.
- Affiliations
- University of Science and Technology of China (CN)
- University of Pennsylvania (US)
- Harvard University (US)
- Corresponding author
- Zhang, Juan
- Liu, Qiang
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 109
- Issue
- 6
- Pages
- 957-970.e8
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W3124009158
- Cited by
- 165
- References
- 0
- Citations by year
- 2026: 28 · 2025: 32 · 2024: 35 · 2023: 29 · 2022: 30 · 2021: 11
- FWCI
- 12.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 381 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Key Research and Development Program of China (2020YFA0509300)
- Fundamental Research Funds for the Central Universities
- Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology (2018CXFX005)
- National Natural Science Foundation of China (31871082, 82071185, 91849101)
- Natural Science Foundation of Anhui Province (2008085QC117)
- Chinese Academy of Sciences (QYZDB-SSW-SMC035, XDB39000000)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- astrocytes, apolipoprotein E, microRNA transfer, histone acetylation, H3K27ac, memory consolidation, epigenetic regulation, acetyl-CoA, APOE ε4, APOE3, immediate early genes, astrocyte-neuron metabolic coupling
- MeSH terms
- Memory Consolidation, Acetylation, Animals, Apolipoproteins E, Astrocytes, Cell Line, Cholesterol, Gene Expression Regulation, Histones, Humans, Mice, Inbred C57BL, Neurons, Epigenesis, Genetic, Mice
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