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Reprogramming astrocytic NDRG2/NF-κB/C3 signaling restores the diabetes-associated cognitive dysfunction

Summary

This study found that regular exercise helps protect the brain of diabetic people from cognitive decline by boosting a protein called NDRG2 in astrocytes (brain support cells). The research shows that NDRG2 works by blocking harmful immune responses that damage synapses (connections between brain cells). In diabetic mice, exercise improved memory and learning ability while increasing NDRG2 levels, while blocking this protein reversed these benefits.

Background

Diabetes-associated cognitive dysfunction (DACD) affects 13.5% of diabetic individuals and can progress to dementia. Exercise is known to improve cognitive function through BDNF expression and neuronal synaptic plasticity. The role of astrocytic NDRG2 in protecting against DACD remains unclear.

Objective

To explore the protective effects of exercise on DACD in diabetic mice and identify NDRG2 as a potential regulator of neuronal synaptic function through the NF-κB/C3 signaling pathway.

Results

Exercise reversed neuronal synaptic injury and upregulated astrocytic NDRG2 in diabetic mice, improving cognitive function. NDRG2 deficiency aggravated complement C3 activation via NF-κB phosphorylation, causing synaptic injury. NDRG2 overexpression inhibited C3 activation, reducing synaptic injury. C3aR blockade rescued dendritic spine loss and cognitive deficits. Diabetic patients showed lower DSST scores and elevated serum C3 levels.

Conclusion

NDRG2 acts as a regulator of astrocytic-neuronal interaction via the NF-κB/C3/C3aR signaling pathway to restore synaptic function and ameliorate cognitive dysfunction in diabetes. Exercise-induced NDRG2 expression provides neuroprotection against DACD through complement cascade inhibition.
  • Published in:eBioMedicine,
  • Study Type:Experimental Animal Study with Human Clinical Data,
  • Source: 37329577
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