Activated AMPK mitigates diabetes-related cognitive dysfunction by inhibiting hippocampal ferroptosis

Area of Science:

• Neuroscience
• Metabolic Disorders
• Cellular Biology

Background:

• Type 2 diabetes (T2D)-associated cognitive dysfunction (TDACD) is a growing concern.
• The exact mechanisms driving TDACD require further investigation.
• Ferroptosis, implicated in neurodegeneration and diabetes-related organ damage, has an unclear role in TDACD.

Purpose of the Study:

• To investigate the role of ferroptosis in the cognitive dysfunction observed in a mouse model of Type 2 diabetes.
• To explore the potential therapeutic effects of targeting ferroptosis and the AMPK pathway.

Main Methods:

• A high-fat diet combined with streptozotocin (HFD-STZ) was used to establish a T2D mouse model.
• Ferroptosis markers were analyzed in hippocampal neurons, microglia, and astrocytes.
• Mice were treated with a ferroptosis inhibitor (liproxstatin-1) and an AMPK agonist to assess cognitive function and molecular changes.

Main Results:

• Ferroptosis was primarily activated in hippocampal neurons of HFD-STZ mice, evidenced by altered transferrin receptor, ferritin, GPX4, and SLC7A11 levels.
• Inhibition of ferroptosis with liproxstatin-1 improved cognitive function and reduced oxidative stress.
• Decreased AMPK activation was observed in HFD-STZ mice; AMPK agonist treatment enhanced AMPK and GPX4 expression, reduced LCN2, and improved spatial learning.

Conclusions:

• Neuronal ferroptosis in the hippocampus is a key contributor to cognitive impairment in HFD-STZ mice.
• AMPK activation shows potential in mitigating hippocampal ferroptosis and ameliorating cognitive deficits in diabetic conditions.