2. Academic Validation
  3. Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory

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

  • Neuron. 2021 Mar 17;109(6):957-970.e8. doi: 10.1016/j.neuron.2021.01.005.
Xiaohui Li 1,  Juan Zhang 2,  Dingfeng Li 3,  Cheng He 1,  Keqiang He 4,  Tian Xue 5,  Lili Wan 6,  Chi Zhang 7,  Qiang Liu 8
Affiliations

Affiliations

  • 1 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 2 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei 230026, China. Electronic address: zj2014@ustc.edu.cn.
  • 3 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei 230029, China.
  • 4 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China.
  • 5 Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 6 Department of Biochemistry and Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
  • 7 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • 8 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei 230026, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650201, China. Electronic address: liuq2012@ustc.edu.cn.
PMID: 33503410 DOI: 10.1016/j.neuron.2021.01.005
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.

Keywords

ApoE; acetyl-CoA; cholesterol metabolism; histone acetylation; memory consolidation; miRNA.

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