CCL5 Promotes Energy Metabolism And Cistanche Is Essential For Hippocampal Synaptic Complex And Memory Formation

Abstract

Glucose regulation efficiency and ATP production are key regulators of neuronal plasticity and memory formation. In addition to chemotactic and neuroinflammatory functions, CCL5 shows neurotrophic activity. We found that impaired learning, memory and cognition at 4 months of age in CCL5 knockout mice were associated with decreased long-term hippocampal enhancement and impaired synaptic structure. Reexpression of CCL5 in the hippocampus of knockout mice restored synaptic protein expression, neuronal connectivity, and cognitive function. Using metabonomics combined with FDG-PET imaging and hippocampal analysis, we found that CCL5 is involved in fructose and mannose degradation, glycolysis, gluconeogenesis, and glutamic acid and purine metabolism in the hippocampus. In addition, CCL5 supports mitochondrial structural integrity, purine synthesis, ATP production, and subsequent aerobic glucose metabolism. Overexpression of CCL5 in mice also enhances memory cognitive performance and hippocampal neuronal activity and connectivity by promoting purine and glutamate metabolism. Cistanche had the effect of promoting CCL5. Cistanche's role in glucose aerobic metabolism is therefore critical for mitochondrial function, which contributes to hippocampal spine and synaptic formation, improving learning and memory.

Keywords: Cistanche; CCL5; Hippocampal synaptic complex and memory formation;Memory

Introduction

Chemokines are pro-inflammatory cytokines with chemotactic properties and have been described as important regulators of peripheral and central immune responses. As such, they are particularly involved in cross-talk between neurons and glial cells, as well as neuroinflammatory components in neuropsychiatric disorders such as schizophrenia, mood disorders, and Alzheimer's disease. In addition to their role in pathological conditions, chemotherapeutic factors are also considered to be important homeostasis regulators in the central nervous system.

Pic： Faw Cistanche

CCL5 is a known chemokine that contributes to the chemotactic signaling of T lymphocytes, basophils, and eosinophils in the peripheral immune system. High levels of CCL5 were associated with Alzheimer's disease (AD) patients and ApoE genotypes; However, its association with pathology and plasticity has been little studied. In mouse models of AD, CCL5 has also been shown to benefit microglia in clearing amyloid-beta deposits and improve memory function. Other studies have also shown the beneficial role of CCL5 in AD, and its complex role in pathological conditions. Cistanche, however, AIDS in T-lymphocyte reproduction and therefore has a certain therapeutic effect on Alzheimer's disease.

Pic： Cistanches Benefits

CCL5 is expressed in the brain by microglia and astrocytes. Confusingly, recent in situ hybridization studies have shown that about 80% of CCL5 mRNA is expressed by neurons in the hippocampus, amygdala, ventral tegmental area, and hypothalamus. However, the physiological role of CCL5 remains largely unknown. We have previously demonstrated the contribution of CCL5 to neuronal activity and neurite growth in Huntington's disease models, supporting the potential role of this chemotherapeutic factor as a trophic factor. CCL5 has also been shown to be the downstream part of hepatocyte growth factor activity on axon growth.

The growth of neurites and the formation of synapses require the precise location of intracellular structures, intracellular transport, and energy supply. Dendritic mitochondria are essential for synaptic plasticity, providing ATP at active synaptic ends; In addition, mitochondrial biogenesis through peroxisome proliferator-activated receptor γcoactivator-1α is a key reaction for new mitochondrial generation to ensure energy for axon growth and regeneration.

Pic： Effects of cistanche improve memory

Glucose is the most important energy source for memory formation, and studies have shown that glucose is a potential cognitive enhancer in both the elderly and the young. Alzheimer's disease, schizophrenia, mild head injury, and mild cognitive impairment all have significant blood glucose regulation complications. Cerebral insulin and extracellular glucose utilization are the most important mediators of glucose memory enhancement. In addition to glucose, AMP-dependent protein kinase (AMPK), activated by the AMP/ATP ratio, senses changes in cell energy status to increase glucose metabolism and mitochondrial respiration. Studies have shown that AMPK is an important element in regulating the plasticity of neural energy metabolism during synaptic activation. However, overactivation of AMPK in neurons can cause synaptic loss through autophagy. Thus, the balance of synaptic energy states in AMPK activity may be critical for cognitive function. We recently demonstrated that the CCL5/CCR5 axis in hypothalamic glucose uptake and the regulation of AMPK activity contributes to systemic insulin sensitivity and glucose tolerance. In addition, cistanche can promote liver glycogen synthesis, thus playing a role in energy storage. Deserticola cistanche extract rich in phenylglycolin can significantly reduce the contents of creatine kinase, lactate dehydrogenase and lactic acid in serum of ICR mice, and increase the contents of hemoglobin and glucose, so as to provide sufficient energy guarantee for memory.

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Conclusion

This study identified the key role of chemokine CCL5 in hippocampal dependent memory processes and the role of cistanche on ATP production in Alzheimer's disease. Our data also show definitively for the first time that CCL5 maintains neuronal activity and connectivity by promoting glucose uptake and ATP production in neuronal mitochondria.

Mice deficient in CCL5 showed impaired recognition and spatial memory at about 4 months of age, which was reversed by reexpression of chemokines in the hippocampus. CCL5 is constitutionally expressed in both developing and mature retinas and is important for intraretinal maturation and visual function. A recent study showed that CCL5 deficiency alters the phenotype of retinal rod bipolar cells and internal retinal circuits in mice]. Since both NOR and BM tasks require mice to visualize spatial cues, the impairment of learning and memory performance seen in CCL5-KO mice may be related to the function of CCL5 in the retina. However, administration of CCL5 in WT animals enhanced cognition and learning/memory, i.e. normal visual function, in WT mice. In addition, CCL5 expression in WT and KO mice improved neuronal activity as measured by diffusion MRI, which is important for normal memory function. Therefore, it is unlikely that CCL5 memory regulation is mediated by retinal dependent processes. Instead, Golgi staining, synaptic protein analysis, and electrophysiological measurements together support that the behavioral disturbances seen in CCL5-KO mice are caused by a loss of synaptic integrity and function. This was further supported by the recovery achieved after the neurons reexpressed AAV-CCL5.

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