Cited by 165Neuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration MechanismsCholesterol and Lipid Metabolism

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Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory

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Li, Xiaohui, Zhang, Juan, Li, Dingfeng, He, Cheng, He, Keqiang, Xue, Tian, Wan, Lili, Zhang, Chi, Liu, Qiang·2021·Neuron

DOI 10.1016/j.neuron.2021.01.005

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Abstract

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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BackgroundInfluential
Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis
More, S., Bonnereau, J., Wouters, D., Spotbeen, X., Karras, P., Rizzollo, F., Killian, T., Venken, T., Naulaerts, S., Vervoort, E., et al. (2024) · Science Advances · doi:10.1126/sciadv.adp6164 · Cited by 25
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Influential
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Background
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“Immunofluorescence Staining Immunofluorescence staining was performed as described previously (Li et al., 2021).”
MethodSelf-citation
Astrocyte Lipid Droplet Dynamics Orchestrate Neurological Disorders and Therapeutic Horizons
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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).”
Background
Targeting ApoE–KCC2 Signaling Rescues GABAergic Synaptic Dysfunction and Depression-like Behaviors in Mice
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InfluentialSelf-citation
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Influential
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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).”
Background
MicroRNAs on the move: microRNAs in astrocyte-derived ApoE particles regulate neuronal function
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Investigating the shared genetic architecture between frailty and insomnia
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Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers
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Mechanistic insights on non-coding RNAs in learning and memory.
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HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer’s disease
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ApoE maintains neuronal integrity via microRNA and H3K27me3-mediated repression
Tan, J., Tan, Y.-Y., Ngian, Z., Chong, S. Y., Rao, V. K., Wang, J., Zeng, X., & Ong, C. (2024) · iScience · doi:10.1016/j.isci.2024.109231 · Cited by 5

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
ORCID: Li, Xiaohui
Zhang, Juan
Li, Dingfeng
He, Cheng
He, Keqiang
Xue, Tian
Wan, Lili
Liu, Qiang
Venue: Neuron
Publisher: Elsevier BV
Published: 2021-03
Volume: 109
Issue: 6
Pages: 957-970.e8
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/j.neuron.2021.01.005
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › 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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Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory

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