Reprogramming astrocytic NDRG2/NF-κB/C3 signaling restores the diabetes-associated cognitive dysfunction
Tao Jiang1, Yansong Li2, Shuxuan He2
1Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China; Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China.
Ebiomedicine
|June 17, 2023
Summary
Exercise improves cognitive function in diabetic mice by restoring neuronal synaptic plasticity and regulating NDRG2. This protein acts as a key regulator in the NF-κB/C3/C3aR signaling pathway, offering a potential therapeutic target for diabetic cognitive dysfunction.
Area of Science:
- Neuroscience
- Endocrinology
- Molecular Biology
Background:
- Diabetic cognitive dysfunction (DACD) is a serious complication of diabetes, often leading to dementia.
- Understanding the molecular mechanisms underlying DACD is crucial for developing effective interventions.
- Neuronal synaptic plasticity is impaired in DACD, contributing to cognitive decline.
Purpose of the Study:
- To investigate the protective effects of exercise on DACD in diabetic mice.
- To explore the role of NDRG2 in reversing pathological changes in neuronal synapses associated with DACD.
- To elucidate the molecular pathways, including complement cascades, involved in DACD and exercise-induced recovery.
Main Methods:
- Standardized moderate-intensity treadmill exercise was performed on diabetic mice.
- Multi-omics approaches (transcriptome, proteome sequencing) combined with WGCNA and GSEA were employed.
- Techniques including Golgi staining, Western blotting, immunofluorescence, and electrophysiology were used to validate findings. NDRG2 function was assessed via in vivo manipulation. Cognitive function was evaluated using the DSST.
Main Results:
- Exercise ameliorated DACD by reversing synaptic injury and restoring astrocytic NDRG2 levels in diabetic mice.
- NDRG2 deficiency exacerbated complement C3 activation and NF-κB phosphorylation, leading to synaptic injury and cognitive deficits.
- NDRG2 overexpression inhibited complement C3, promoting astrocytic remodeling and attenuating synaptic injury. C3aR blockade also rescued cognitive deficits. Elevated C3 levels and lower DSST scores were observed in diabetic patients.
Conclusions:
- NDRG2 plays a critical role in improving cognitive function in diabetic mice through multi-omics insights.
- NDRG2 expression is linked to cognitive function and complement cascade activation in DACD.
- NDRG2 regulates astrocytic-neuronal interaction via the NF-κB/C3/C3aR pathway to restore synaptic function in diabetic conditions.
