Diabetes mellitus is associated with cognitive impairment characterized by memory loss and cognitive inflexibility. Recent studies have revealed that ChemR23 is implicated in both diabetes mellitus and Alzheimer's disease. However, the impact of ChemR23 on diabetes-associated cognitive impairment remains elusive. In this study, we explored the longitudinal changes of ChemR23 expression and cognitive function in STZ-induced type 1 diabetic mice and leptin receptor knockout type 2 diabetic mice at different ages. We also treated diabetic mice with ChemR23 agonists RvE1 or chemerin-9 to explore whether ChemR23 activation could alleviate diabetes-associated cognitive impairment. The underlying mechanism was further investigated in diabetic mice with genetic deletion of ChemR23. The results showed that ChemR23 expression was decreased along with aging and the progression of diabetes, suggesting that abnormal ChemR23 signaling may be involved in diabetes-associated cognitive impairment. Administration of RvE1 or chemerin-9 ameliorated oxidative stress and inhibited NLRP3 inflammasome activation through Nrf2/TXNIP pathway, and ultimately alleviated cognitive impairment in diabetic mice. Depletion of ChemR23 in diabetic mice abolished the beneficial effects of RvE1 and chemerin-9, and exacerbated cognitive impairment via increasing oxidative stress and activating NLRP3 inflammasome. Collectively, our data highlight the crucial role of ChemR23 signaling in diabetes-associated cognitive impairment via regulating oxidative stress and NLRP3 inflammasome, and targeting ChemR23 may serve as a promising novel strategy for the treatment of diabetes-associated cognitive impairment.

Background: Increasing evidence has suggested that alterations in the gut microbiome are correlated with autoimmune neurologic disorders, yet the causal relationship between them has yet to be established.Methods: From the published genome-wide association study (GWAS) summary statistics, we obtained data on the gut microbiota and three autoimmune neurologic disorders (Multiple Sclerosis, Guillain-Barré Syndrome, and Myasthenia Gravis). We then implemented a two-sample Mendelian Randomization (MR) to determine the causal relationship between the gut microbiota and the diseases. To validate the results, we conducted a series of sensitivity analyses. Finally, to verify the direction of causality, a reverse-causality analysis was done.Results: We discovered that a higher relative abundance of the genus Ruminococcus2 (OR: 1.213, 95% CI: 1.006–1.462, p = 0.043, P_FDR = 0.048) and the genus Roseburia (OR: 1.255, 95% CI: 1.012–1.556, p = 0.038, P_FDR = 0.048) were associated with a higher risk of MS. Furthermore, the higher the abundance of the class Mollicutes (OR: 3.016, 95% CI: 1.228–7.411, p = 0.016, P_FDR = 0.021), the genus Eubacterium (hallii group) (OR: 2.787, 95% CI: 1.140–6.816, p = 0.025, P_FDR = 0.025), and the phylum Tenericutes (OR: 3.016, 95% CI: 1.228–7.411, p = 0.016, P_FDR = 0.021) was linked to a greater probability of GBS. Additionally, the higher the abundance of the genus Ruminococcaceae UCG005 (OR: 2.450, 95% CI: 1.072–5.598, p = 0.034, P_FDR = 0.036), the genus Holdemania (OR: 2.437, 95% CI: 1.215–4.888, p = 0.012, P_FDR = 0.024), genus Lachnoclostridium (OR: 3.681, 95% CI: 1.288–10.521, p = 0.015, P_FDR = 0.025) and the genus Eubacterium (ruminantium group) (OR: 2.157, 95% CI: 1.211–3.843, p = 0.003, P_FDR = 0.016) correlated with a greater chance of MG occurrence. No SNPs were identified as outliers through sensitivity analysis. Then, the results of the reverse MR analysis did not indicate any reverse causality.Conclusion: Our findings demonstrate a causal relationship between the gut microbiota and three autoimmune neurologic disorders, providing novel insights into the mechanisms of these autoimmune neurologic disorders that are mediated by gut microbiota.

Mutations in HSPB1 are known to cause Charcot-Marie-Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). In this study, we presented three patients with mutation in HSPB1 who were diagnosed with dHMN. Proband 1 was a 14-year-old male with progressive bilateral lower limb weakness and walking difficulty for four years. Proband 2 was a 65-year-old male with chronic lower limb weakness and restless legs syndrome from the age of 51. Proband 3 was a 50-year-old female with progressive weakness, lower limbs atrophy from the age of 44. The nerve conduction studies (NCS) suggested axonal degeneration of the peripheral motor nerves and needle electromyography (EMG) revealed chronic neurogenic changes in probands. Open sural nerve biopsy for proband 2 and the mother of proband 1 showed mild to moderate loss of myelinated nerve fibers with some nerve fiber regeneration. A novel p.V97L in HSPB1 was identified in proband 3, the other two variants (p.P182A and p.R127W) in HSPB1 have been reported previously. The functional studies showed that expressing mutant p.V97L HSPB1 in SH-SY5Y cells displayed a decreased cell activity and increased apoptosis under stress condition. Our study expands the clinical phenotypic spectrum and etiological spectrum of HSPB1 mutation.