Estrogen deficiency after menopause is associated with autonomic nervous changes, leading to memory impairment and increased susceptibility to Alzheimer’s disease (AD). Royal jelly (RJ) from honeybees (Apis mellifera) has estrogenic activity. Here, we investigated whether RJ can improve behavior, cholinergic and autonomic nervous function in ovariectomized (OVX) cholesterol-fed rabbits. OVX rabbits on high-cholesterol diet were administered with RJ for 12 weeks. The results showed that RJ could significantly improve the behavioral deficits of OVX cholesterol-fed rabbits and image structure of the brain. RJ reduced body weight, blood lipid, as well as the levels of amyloid-beta (Aβ), acetylcholinesterase (AchE), and malonaldehyde (MDA) in the brain. Moreover, RJ also increased the activities of choline acetyltransferase (ChAT) and superoxide dismutase (SOD) in the brain, and enhanced heart rate variability (HRV) and Baroreflex sensitivity (BRS) in OVX cholesterol-fed rabbits. Furthermore, RJ was also shown to reduce the content of Evans blue and the expression levels of Aβ, beta-site APP cleaving enzyme 1(BACE1), and receptor for advanced glycation end products (RAGE), and increase the expression level of LDL(low density lipoprotein) receptor-related protein 1 (LRP-1) in the brain. Our findings suggested that RJ has beneficial effects in neurological disorders of postmenopausal women, which were associated with reducing cholesterol and Aβ deposition, enhancing the estrogen levels and the activities of cholinergic and antioxidant systems, and ameliorating the blood–brain barrier (BBB) permeability and restoring autonomic nervous system.

Introduction: Cognitive impairment is a common complication of chronic kidney disease (CKD), but its underlying mechanisms are not fully understood. This study aims to investigate the glymphatic system function in CKD patients with and without cognitive impairment (CI) by analyzing the coupling between the global blood oxygen level-dependent (gBOLD) signal and the cerebrospinal fluid (CSF) signal using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Twenty-nine patients with CKD were enrolled (19 with CI and 10 without), along with 22 healthy controls (HCs). All patients underwent high-resolution structural MRI and rs-fMRI scans. The gBOLD–CSF coupling was quantified by calculating the maximum negative correlation within a predefined time-lag range between the gBOLD signal and the fourth ventricular CSF signal. The gBOLD-CSF coupling was compared between the CKD and HC groups using analysis of covariance (ANCOVA), adjusting for age, sex, education, and mean framewise displacement (FD). The difference between patients with CKD with and without CI was assessed using ANCOVA, after adjusting for age, sex, education, hypertension, diabetes, and mean FD. Partial correlation analysis was performed to explore the associations between gBOLD-CSF coupling and clinical indicators, such as estimated glomerular filtration rate (eGFR), Montreal Cognitive Assessment (MoCA) scores, and other laboratory data. Results: After adjusting for covariates, gBOLD-CSF coupling was significantly lower in the CKD group than in the HC group ( β = −0.178, p = 0.003). This finding remained robust in sensitivity analyses adjusting for hypertension and diabetes. Within the CKD group, patients with CI had significantly lower gBOLD-CSF coupling than those without CI ( β = −0.135, p = 0.040). Correlation analyses revealed that gBOLD-CSF coupling tended to be positively associated with hemoglobin, MoCA score, and eGFR, and negatively associated with blood urea and creatinine; however, none of these correlations reached statistical significance after false discovery rate correction (all q > 0.05). Conclusion: Patients with CKD exhibit impaired glymphatic system function, manifested as reduced gBOLD-CSF coupling, which is associated with the severity of CI. These findings support the hypothesis that impaired glymphatic clearance may contribute to cognitive decline in CKD via the kidney-brain axis. Larger longitudinal studies are needed to validate its clinical significance.