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CD33, a transmembrane receptor of the innate immune system, is expressed on the surface of microglial cells. Genome-wide association studies (GWAS) have linked variants in CD33 to Alzheimer’s disease risk, and both disease-promoting and protective alleles have been identified.

Uniprot lists three isoforms of human CD33. The 364-amino acid isoform, referred to as full-length CD33 or CD33M, is considered the canonical version. A second isoform, CD33m (237 amino acids) lacks the ligand-binding domain of CD33 and is produced by exon 2 skipping. The protective allele of CD33 appears to increase the generation of this isoform at the expense of the full-length form (reviewed by Estus et al., 2019). In the third isoform, CD33-3 (310 amino acids), the 56-amino-acid sequence encoded by exon 7 is replaced by two amino acids, valine and arginine.

Mouse CD33—like human CD33—is found on microglia (Bhattacherjee et al., 2019). Its expression is downregulated in aging 5xFAD mice (Griciuc et al., 2019), and genetic deletion of CD33 was found to decrease plaque burden in this (Griciuc et al., 2019) and another (Griciuc et al., 2013) mouse model of amyloidosis. Human and mouse CD33 have similar extracellular domains (~60 percent shared amino acids) but differ in their cytoplasmic domains (Tchilian et al., 1994). Two isoforms of CD33 have been identified in mice. CD33M (isoform-1), the full-length, 403-amino acid isoform, is considered the canonical version. CD33m (isoform-2) has 334-amino acids and is produced by alternative splicing, in which skipping of exon 6 causes a frameshift and an early stop codon. (Despite the identical nomenclature, the “m” versions of human and mouse CD33 represent very different isoforms, with the human version lacking the extracellular ligand-binding domain and the mouse isoform having a modified intracellular sequence.)