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

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

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.

Highlights

Chemokines are pro-inflammatory cytokines with chemoattractant properties that have been described as important regulators of peripheral and central immune responses [1,2,3]
Behavioral investigations demonstrated that the learning memory performance of CCL5-knock out (CCL5-KO) mice in Barnes maze (BM) was not different from wild type (WT) at 2 months of age (Supplementary Fig. 1a); the KO animals gradually showed impairments in learning and memory from 3 to 4 months of age (Fig. 1, Supplementary Fig. 1b)
In the novel object recognition (NOR) task, the total exploration time and the preference for the new object were significantly lower in CCL5-KO mice (Fig. 1b, c, Fig. 1a shows the movement track of both groups of mice in the open field)

Summary

Introduction

Chemokines are pro-inflammatory cytokines with chemoattractant properties that have been described as important regulators of peripheral and central immune responses [1,2,3]. As such, they are involved in the cross-talk between neurons and glial cells as well as neuroinflammatory components in neuropsychiatric diseases such as schizophrenia, mood disorders, and Alzheimer’s disease (AD) [4]. They are involved in the cross-talk between neurons and glial cells as well as neuroinflammatory components in neuropsychiatric diseases such as schizophrenia, mood disorders, and Alzheimer’s disease (AD) [4] In addition to such roles in pathological conditions, chemokines are thought to be important homeostatic regulators in the central nervous system [2, 3].

Methods

Results

Conclusion