SCD2 Alleviates Diabetes-Associated Cognitive Dysfunction by Improving Microglial Lipid Metabolism

Area of Science:

• Neuroscience
• Metabolic Neuroscience
• Immunology

Background:

• Diabetes-associated cognitive dysfunction (DACD) mechanisms are unclear, with microglial metabolic dysfunction as a key factor.
• Stearoyl-CoA desaturase 2 (SCD2) role in microglial lipid metabolism and DACD requires investigation.

Purpose of the Study:

• To investigate if stearoyl-CoA desaturase 2 (SCD2) alleviates cognitive impairment by modulating microglial lipid metabolism and function.
• To explore SCD2's therapeutic potential for diabetes-associated cognitive dysfunction.

Main Methods:

• Bioinformatics analysis of single-cell RNA-seq data (GSE201644) identified SCD2 downregulation in diabetic microglia.
• In vivo studies involved hippocampal SCD2 overexpression in a type 2 diabetes mouse model using AAV injection.
• In vitro studies utilized high glucose-treated BV2 microglia-like cells with SCD2 overexpression or oleic acid supplementation.

Main Results:

• Diabetic microglia showed reduced SCD2, impaired mitochondrial function, and increased lipid droplet accumulation.
• SCD2 overexpression or oleic acid supplementation rescued mitochondrial function, reduced lipid accumulation, and decreased inflammation.
• In vivo hippocampal SCD2 overexpression attenuated neuroinflammation, preserved synaptic integrity, and improved cognitive function in diabetic mice.

Conclusions:

• SCD2 is crucial for maintaining microglial lipid and mitochondrial homeostasis in diabetes.
• Restoring SCD2 function mitigates neuroinflammation and synaptic deficits, rescuing cognitive impairment in DACD.
• SCD2 represents a potential therapeutic target for managing diabetes-associated cognitive dysfunction.