Xanthohumol improves cognitive impairment by regulating miRNA-532-3p /Mpped1 in ovariectomized mice

Rationale Studies have shown the potential neuroprotective effect of xanthohumol, while whether xanthohumol has the ability of repairing cognitive impairment and its underlying mechanism still remains obscure. Objectives To unravel the mechanism of xanthohumol repairing cognitive impairment caused by estrogen deprivation. Methods C57BL/6 J female mice that underwent bilateral ovariectomy to establish cognitive decline model were randomly divided into three xanthohumol-treated groups and a saline-treated model group. For identifying the neuroprotective function of xanthohumol, Morris water maze (MWM) test and open field test (OFT) were conducted. After extracting total RNA of mouse hippocampus of different groups, mRNA-seq and microRNA (miRNA)-seq analysis were performed, and the differentially expressed miRNAs (DEMIs) and their target genes were further validated by qPCR. MiR-532-3p and its downstream gene Mpped1 were screened as targets of xanthohumol. Influence of miR-532-3p/Mpped1 to cognitive ability was examined via MWM test and OFT after stereotactic brain injection of Mpped1 overexpressed adeno-associated virus. The regulation of miR-532-3p on Mpped1 was confirmed in hippocampal neuronal cell line HT22 by luciferase reporter gene assay. Results Xanthohumol treatment reversed the cognitive decline of OVX mice according to behavioral tests. By comparing miRNA levels of xanthohumol-treated groups with saline-treated group, we found that the main changed miRNAs were miR-122-5p, miR-532-3p, and miR-539-3p. Increased miR-532-3p in OVX mice was suppressed by xanthohumol treatment. Furthermore, the downstream gene of miR-532-3p, Mpped1 , was also increased by xanthohumol and showed the capability of relieving cognitive impairment of OVX mice after overexpressed in hippocampus. The 3′ untranslated region of Mpped1 was identified as the target region of miR-532-3p, and agomiR-532-3p remarkably reduced the expression of Mpped1 mRNA. Conclusions Xanthohumol has the ability of repairing cognitive impairment through removing the inhibition of miR-532-3p on Mpped1 in mouse hippocampus. This finding not only advances the understanding of neuroprotective mechanism of xanthohumol, but also provides novel treatment targets for dementia of postmenopausal women.