Chronic d-ribose and d-mannose overload induce depressive/anxiety-like behavior and spatial memory impairment in mice

Ke Xu,Peng Xie,Juncai Pu,Mingyang Wang,Wei Zhou,Haiyang Wang

doi:10.1038/s41398-020-01126-4

Abstract

The effects of different forms of monosaccharides on the brain remain unclear, though neuropsychiatric disorders undergo changes in glucose metabolism. This study assessed cell viability responses to five commonly consumed monosaccharides—D-ribose (RIB), D-glucose, D-mannose (MAN), D-xylose and L-arabinose—in cultured neuro-2a cells. Markedly decreased cell viability was observed in cells treated with RIB and MAN. We then showed that high-dose administration of RIB induced depressive- and anxiety-like behavior as well as spatial memory impairment in mice, while high-dose administration of MAN induced anxiety-like behavior and spatial memory impairment only. Moreover, significant pathological changes were observed in the hippocampus of high-dose RIB-treated mice by hematoxylin-eosin staining. Association analysis of the metabolome and transcriptome suggested that the anxiety-like behavior and spatial memory impairment induced by RIB and MAN may be attributed to the changes in four metabolites and 81 genes in the hippocampus, which is involved in amino acid metabolism and serotonin transport. In addition, combined with previous genome-wide association studies on depression, a correlation was found between the levels of Tnni3k and Tbx1 in the hippocampus and RIB induced depressive-like behavior. Finally, metabolite–gene network, qRT-PCR and western blot analysis showed that the insulin-POMC-MEK-TCF7L2 and MAPK-CREB-GRIN2A-CaMKII signaling pathways were respectively associated with RIB and MAN induced depressive/anxiety-like behavior and spatial memory impairment. Our findings clarified our understanding of the biological mechanisms underlying RIB and MAN induced depressive/anxiety-like behavior and spatial memory impairment in mice and highlighted the deleterious effects of high-dose RIB and MAN as long-term energy sources.

Highlights

With the improvement in global living standards, and apart from genetic factors, excess sugar consumption has been proposed as a potential risk factor for metabolic diseases[1]
Together with the Gene Ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), co-expression, and protein–protein interaction (PPI) network results, the findings suggest that RIB is involved in the “Wnt signaling pathway” (Fig. 4c) and that MAN is involved in the “calcium signaling pathway” (Fig. 4d)
Given that PPI, co-expression network analysis, and Ingenuity Pathways Analysis (IPA) network analysis indicated that aldehyde dehydrogenase 1 family member a2 (Aldh1a2) was correlated with TCF7L2, we examined the mRNA levels of Aldh1a2 in the 0.4 and 4 g/kg RIB groups

Summary

Introduction

With the improvement in global living standards, and apart from genetic factors, excess sugar consumption has been proposed as a potential risk factor for metabolic diseases[1]. D-ribose (RIB), D-mannose (MAN), D-xylose (XYL), and L-arabinose (ARA), five hexoses or pentoses, have been increasingly used as food additives or nutritional supplements. MAN is a C-2 epimer of glucose that occurs naturally in many plants and fruits, and it has been used as a nonantibiotic treatment for bacterial urinary tract infections[8]. It plays a central role in energy generation, storage, and cell regulation[9]. It has been reported that the average urine RIB level of Alzheimer’s disease (AD) patients (96.91 ± 17.36 μmol/L) was higher than that of cognitively normal participants (55.29 ± 7.08 μmol/L)[12]. Several studies have reported that RIB causes cognitive impairment[15,16], the physiopathological mechanisms are still poorly understood

Methods

Results

Conclusion