CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Mechanisms linking CD33 variants to Alzheimer Disease (AD) are unclear.
• The CD33^M splice isoform is upregulated in individuals with CD33 risk alleles.
• Microglial function is modulated by CD33 variants in AD pathogenesis.

Purpose of the Study:

• To delineate how the CD33^M splice isoform modulates microglial function in Alzheimer Disease.
• To investigate the interaction between CD33^M, clusterin (CLU), and amyloid-beta (Aβ) oligomers.
• To identify potential therapeutic targets within the CD33:CLU:Aβ axis.

Main Methods:

• Structural, cellular, and genetic analyses were employed.
• CD33^M ectodomain dimerization and ligand-binding properties were assessed.
• The impact of CD33^M:CLU binding on microglial phagocytosis and amyloid plaque clearance was evaluated in human monocytes.
• A soluble CD33^M ectodomain fragment (sCD33^M) was identified.
• Genetic analyses correlated CD33:CLU interaction with amyloid burden, cognition, and AD risk.

Main Results:

• CD33^M ectodomain dimerizes, binding multi-sialylated molecules.
• Clusterin (CLU) and Aβ oligomers bind specifically to CD33^M with high affinity.
• CD33^M:CLU binding in monocytes suppresses Aβ phagocytosis and impairs amyloid plaque clearance.
• A soluble fragment, sCD33^M, was identified and is absent in CD33^m-expressing cells.
• Genetic data confirm CD33:CLU interaction influences amyloid burden, cognition, and AD risk.

Conclusions:

• A mechanistic CLU:Aβ:CD33^M axis is defined in Alzheimer Disease.
• CD33^M dimerization and ligand-binding sites represent potential therapeutic targets.
• Understanding this axis provides insights into microglial dysfunction in AD.