Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Complement system activation is implicated in neurodegenerative diseases (NDDs) like Alzheimer's Disease (AD).
• Understanding the source and regulation of complement in the brain is crucial for effective therapeutic targeting in NDDs.

Purpose of the Study:

• To comprehensively map complement gene expression in the human frontal cortex.
• To investigate how AD pathology, sex, and age influence complement expression patterns.

Main Methods:

• Integrated single-nucleus RNA sequencing data from 97 frontal cortex donors (60 AD, 37 controls).
• Analyzed complement expression across nine major cell types.
• Examined the impact of AD, sex, and age on complement gene expression.

Main Results:

• Microglia are the primary source of key complement components (C1Q, C3) in healthy and AD brains, with increased expression in AD.
• AD elevates complement component expression (C1R, C1S, C5, C7) in fibroblasts, pericytes, and astrocytes.
• Complement regulators (CD46, CD55, CD59, CFH) show increased expression in endothelial cells in AD.
• The AD risk gene CLU is highly expressed in astrocytes.
• Sex-specific differences emerge in AD, with females showing greater complement dysregulation.
• Youngest AD individuals exhibit the most severe complement dysregulation.

Conclusions:

• A detailed atlas of complement expression in the AD and control frontal cortex reveals significant dysregulation in AD.
• Female sex is associated with greater complement dysregulation in AD.
• Age-dependent complement dysregulation in AD, particularly in younger individuals, offers insights for therapeutic intervention timing.