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

Reni Ajoy, Yu Chun Lo, Man Hau Ho, You Yin Chen, Yun Wang, Yuan Hao Chen, Chiu Jing-Yuan, Chun Austin Changou, Yuan Chin Hsiung, Hui Min Chen, Tzu Hao Chang, Cheng Yang Lee, Yung Hsiao Chiang, Wen Chang Chang, Barry Hoffer, Szu Yi Chou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish
Pages (from-to)6451-6468
Number of pages18
JournalMolecular Psychiatry
Volume26
Issue number11
DOIs
StateE-pub ahead of print - Apr 2021

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