CD33 is a transmembrane receptor of the innate immune system that is expressed on the surface of peripheral monocytes and microglial cells in the brain. CD33 was first implicated in Alzheimer’s disease genetics in 2008, and in 2011 reached genome-wide significance in large GWAS in the U.S. and Europe. Since then, CD33 has been further validated in independent sample series in Canada, China, and elsewhere, and constitutes a top 10 hit on AlzGene.
CD33 has primarily been studied in the peripheral immune system, where it inhibits proliferation of myeloid cells. More recent network analyses of gene expression patterns in the human brain placed CD33 inside an immune regulatory module together with other proteins relevant to AD, such as TREM2, TYROBP, and MSA4A. CD33 encodes a member of a superfamily called sialic acid-binding immunoglobulin-like lectins (Siglecs). In microglia, CD33 binds extracellular sialylated glycans on other cells or pathogens. Its cytoplasmic domain signals via phosphatidyl-inositol-3 kinase (PI3K) to dampen microglial phagocytosis; by comparison, TREM2 responds to ligand binding by activating PI3K to increase phagocytosis. In mouse models, CD33 has been shown to slow phagocytosis and Aβ clearance.
CD33 expression is elevated in AD brain and has been linked to both amyloid pathology and disease progression. The initial GWAS reported the C allele of the promoter polymorphism rs3865444 of CD33 as increasing AD risk. This SNP was subsequently associated with increased CD33 expression and microglial activation, and with diminished Aβ42 internalization and increased brain amyloid load. Subsequent research identified rs12459419, a protective variant in exon 2 of CD33. This SNP was reported to alter splicing of the CD33 mRNA such that the resulting protein lacks CD33’s sialic acid binding domain and therefore preserves the cell’s ability to take up and clear Aβ. The search for functional CD33 variants and their underlying mechanisms of action is an active area of research.
- Protective Microglial Gene Variant Promotes Phagocytosis
- Large Genetic Analysis Pays Off With New AD Risk Genes
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