2. Academic Validation
  3. CCL5 promotion of bioenergy metabolism is crucial for hippocampal synapse complex and memory formation

CCL5 promotion of bioenergy metabolism is crucial for hippocampal synapse complex and memory formation

  • Mol Psychiatry. 2021 Nov;26(11):6451-6468. doi: 10.1038/s41380-021-01103-3.
Reni Ajoy 1 2,  Yu-Chun Lo 1 2,  Man-Hau Ho 1 2 3,  You-Yin Chen 1 4 5,  Yun Wang 6,  Yuan-Hao Chen 7,  Chiu Jing-Yuan 2,  Chun Austin Changou 8 9 10,  Yuan-Chin Hsiung 10,  Hui-Min Chen 10 11,  Tzu-Hao Chang 12,  Cheng-Yang Lee 13,  Yung-Hsiao Chiang 14 15 16,  Wen-Chang Chang 3,  Barry Hoffer 1 2 17 18,  Szu-Yi Chou 19 20
Affiliations

Affiliations

  • 1 Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan.
  • 2 Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 3 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 4 Department of Biomedical Engineering, National Yang Ming University, No.155, Sec.2, Taipei, Taiwan.
  • 5 Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • 6 Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
  • 7 Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • 8 The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
  • 9 The Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei Medical University, Taipei, Taiwan.
  • 10 Core Facility, Taipei Medical University, Taipei, Taiwan.
  • 11 Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 12 Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan.
  • 13 Research Information Session, Office of Information Technology, Taipei Medical University, Taipei, Taiwan.
  • 14 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 15 Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan.
  • 16 Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan.
  • 17 Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 18 Scientist Emeritus, National Institutes of Health, Bethesda, MD, USA.
  • 19 Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan. sichou@gmail.com.
  • 20 Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. sichou@gmail.com.
PMID: 33931731 DOI: 10.1038/s41380-021-01103-3
Abstract

Glucoregulatory efficiency and ATP production are key regulators for neuronal plasticity and memory formation. Besides its chemotactic and neuroinflammatory functions, the CC chemokine--CCL5 displays neurotrophic activity. We found impaired learning-memory and cognition in CCL5-knockout mice at 4 months of age correlated with reduced hippocampal long-term potentiation and impaired synapse structure. Re-expressing CCL5 in knockout mouse hippocampus restored synaptic protein expression, neuronal connectivity and cognitive function. Using metabolomics coupled with FDG-PET imaging and seahorse analysis, we found that CCL5 participates in hippocampal fructose and mannose degradation, glycolysis, gluconeogenesis as well as glutamate and purine metabolism. CCL5 additionally supports mitochondrial structural integrity, purine synthesis, ATP generation, and subsequent aerobic glucose metabolism. Overexpressing CCL5 in WT mice also enhanced memory-cognition performance as well as hippocampal neuronal activity and connectivity through promotion of de novo purine and glutamate metabolism. Thus, CCL5 actions on glucose aerobic metabolism are critical for mitochondrial function which contribute to hippocampal spine and synapse formation, improving learning and memory.

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