Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in...

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Brain perivascular macrophages are crucial for brain health, but their regulatory mechanisms and functions are not fully understood.
• Identifying key transcription factors is essential for understanding macrophage function in neurological and cerebrovascular diseases.

Purpose of the Study:

• To identify key transcription factors regulating brain perivascular macrophage function.
• To investigate the role of cMAF in brain perivascular macrophage phenotype, function, and communication with vascular cells.
• To explore the role of cMAF in Alzheimer's disease (AD) pathogenesis and its therapeutic potential.

Main Methods:

• Single-cell multi-omics analysis.
• Conditional gene deletion in vivo experiments.
• Functional assays assessing macrophage-endothelial cell communication and vascular function.
• Analysis of human perivascular macrophages in health and AD, including APOE4 carriers.

Main Results:

• Cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) identified as a key transcription factor for brain perivascular macrophages.
• cMAF deletion disrupts macrophage phenotype and impairs communication with endothelial cells via insulin-like growth factor-1 (IGF1) expression.
• cMAF is conserved in human perivascular macrophages and upregulated in AD, enhancing vascular communication, though this is impaired in APOE4 carriers.
• A cMAF polymorphism suggests a protective role against AD.

Conclusions:

• cMAF is a critical regulator of brain perivascular macrophage function and intercellular communication, impacting vascular health.
• The cMAF-IGF1 pathway in perivascular macrophages plays a significant role in AD pathogenesis.
• Targeting cMAF presents a potential therapeutic strategy for neurodegenerative and cerebrovascular diseases.