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Cited by 57Neuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanisms

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

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Ajoy, Reni, Lo, Yu-Chun, Ho, Man-Hau, Chen, You-Yin, Wang, Yun, Chen, Yuan-Hao, Jing-Yuan, Chiu, Changou, Chun Austin +8 more·2021·Molecular Psychiatry
DOI 10.1038/s41380-021-01103-3PMC PMC8760051
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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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  • Monocyte-derived brain macrophages have been reported earlier, but these studies were largely focused on conditions of experimental challenge.

    “Monocyte-derived brain M F have been reported earlier, but these studies were largely focused on conditions of experimental challenge 20-25,59 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [59]

    The Introduction discusses microglia in an Alzheimer’s disease mouse model, and the Methods mention reduced macrophage infiltration after peripheral sensitization. Neither passage addresses whether monocyte-derived brain macrophages had been reported previously or whether those studies were largely conducted under experimental challenge. Searches for monocyte-derived brain macrophages and for macrophage infiltration under challenge found no decisive passage; page numbers were unavailable in our copy. (LLM, conf=0.70)

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Authors
Ajoy, R., Lo, Y.-C., Ho, M.-H., Chen, Y.-Y., Wang, Y., Chen, Y.-H., Jing-Yuan, C., Changou, C. A., Hsiung, Y.-C., Chen, H.-M., Chang, T.-H., Lee, C.-Y., Chiang, Y.-H., Chang, W.-C., Hoffer, B., & Chou, S.-Y.
Affiliations
  • National Health Research Institutes (TW)
  • Tri-Service General Hospital (TW)
  • Taipei Medical University (TW)
  • Taipei Medical University Hospital (TW)
  • National Institutes of Health (US)
Corresponding author
Chou, Szu-Yi
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-04-30
Volume
26
Issue
11
Pages
6451-6468
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-021-01103-3
PMC
PMC8760051
OpenAlex
W3159555503
Cited by
57
References
1
Citations by year
2026: 10 · 2025: 13 · 2024: 17 · 2023: 8 · 2022: 8 · 2021: 1
FWCI
4.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Taipei Medical University Repository (submittedVersion)
Funders
  • Ministry of Science and Technology, Taiwan (MOST 108-2320-B-038-025, MOST 108-2321-B-038-008)
  • National Health Research Institutes (NP-108-PP-01)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
RANTES, chemokines, hippocampus, learning and memory, long-term potentiation, synaptogenesis, glucose metabolism, mitochondrial function, purine metabolism, glutamate metabolism, glycolysis, gluconeogenesis, ATP production, neuroplasticity, neurotrophic activity
MeSH terms
Animals, Hippocampus, Memory, Neuronal Plasticity, Synapses, Long-Term Potentiation, Mice, Knockout, Mice

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