CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk.

Abstract

Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33^M splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33^M ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33^M, but not CD33^m. We show that in human monocytes CD33^M:CLU binding induces CD33^M ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33^M ectodomain fragment (sCD33^M) - absent from CD33^m-expressing cells - which could contribute to the role of CD33^M in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33^M axis, highlighting CD33^M dimerization and ligand-binding sites as potential therapeutic targets.