Microglial metabolic reprogramming drives cognitive decline in heart failure with preserved ejection fraction

Area of Science:

• Neuroscience
• Cardiology
• Metabolic disease

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a growing public health issue.
• HFpEF is increasingly recognized as a contributor to dementia.
• Mechanisms linking cardiometabolic dysfunction to neurodegeneration are poorly understood.

Purpose of the Study:

• To investigate the mechanisms by which HFpEF contributes to cognitive decline.
• To explore the role of microglial metabolic reprogramming in HFpEF-associated neuroinflammation.
• To identify potential therapeutic targets for preventing cognitive impairment in HFpEF.

Main Methods:

• Utilized a clinically relevant murine model of HFpEF.
• Integrated transcriptomics and metabolomics to analyze microglial signaling pathways.
• Performed extracellular flux analysis to assess cellular metabolism.
• Genetically deleted HIF-1α in microglia to evaluate its role.

Main Results:

• HFpEF induced a sustained neuroinflammatory state via microglial metabolic reprogramming.
• HIF-1α signaling was robustly induced in microglia during HFpEF.
• Deletion of microglial HIF-1α attenuated neuroinflammation, preserved white matter integrity, and rescued cognitive performance.
• Sema4D was identified as a HIF-1α-dependent effector linking metabolic stress to white matter injury.

Conclusions:

• HFpEF drives neuroinflammation and cognitive dysfunction through microglial metabolic reprogramming.
• Microglial HIF-1α signaling is a key mediator linking cardiovascular disease to brain injury.
• Targeting microglial HIF-1α represents a potential therapeutic strategy for preventing cognitive decline in cardiometabolic disease.