Astrocytic NDRG2 is a potential guarder for diabetes-associated cognitive dysfunction via regulating complement C3 cascades

Abstract Background Diabetes-associated cognitive dysfunction (DACD), which mainly had three different cognitive characteristics, seriously affect the self-glycemic management and even lead to critical complications such as hypoglycemia, hyperglycemic hyperosmotic coma and ketoacidosis. As most serious stage of DACD, dementia had gradually risen to second leading cause of death in diabetes, indicating the urgency to clarify the integrative pathophysiology of DACD. Methods Here, Y maze and Morris water maze were used to evaluate the learning memory. Based on quantitative transcriptome sequencing and TMT proteome sequencing, we performed WGCNA analysis and GSEA analysis to demonstrate activation of complement cascades induced neurotoxic astrocyte to injury neuronal synaptic plasticity in diabetic mice. Western blotting, immunofluorescence staining, golgi staining and electrophysiology were used to verify the reliability of sequencing data. Results The deficiency of NDRG2 aggravated activation of complement C3 by accelerating the phosphorylation of NF-κB, ultimately lead to synaptic injury and cognitive dysfunction. Conversely, the overexpression of NDRG2 promoted remodeling of neurotoxic astrocyte by inhibiting complement C3, attenuated synaptic injury and cognitive dysfunction. Meanwhile, C3aR blockade rescued dendritic spines loss and cognitive deficits in diabetic mice. Moreover, we estimated cognitive function in diabetic or normal patients by DSST scores, which was negatively correlated with blood glucose, the level of C3 and HOMA-IR in serum. Conclusion Our findings illustrated the effectiveness and integrative mechanism of NDRG2-induced improving cognition from a multi-omics perspective, confirmed the expression of NDRG2 was closely related to cognitive function of diabetic mice and C3 may be a biomarker to predict the progression of DACD in human, which provided a new alerting or therapeutic strategy for patients with cognitive impairment. Trial registration The clinical protocol was registered and approved by the Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University (ID: ChiCTR1900021720).