| Gene | [CD33](/genes/cd33) |
| UniProt | [P20138](https://www.uniprot.org/uniprot/P20138) |
| MW | 40 kDa (unglycosylated) |
| Location | Cell membrane (microglia, myeloid cells) |
| PDB | [5J06](https://www.rcsb.org/structure/5J06) |
CD33 (Siglec-3) is a sialic acid-binding immunoglobulin-like lectin expressed primarily on microglia and myeloid cells. As a member of the Siglec family, CD33 contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that suppress immune cell activation upon ligand binding. CD33 gained prominence in Alzheimer's disease research when genome-wide association studies identified CD33 variants as among the strongest genetic risk factors for late-onset AD.
CD33 is a type I transmembrane protein:
The extracellular domains mediate binding to sialylated glycoproteins and gangliosides, while ITIM signaling recruits SHP-1 and SHP-2 phosphatases to inhibit cellular activation.
CD33 functions as an inhibitory receptor on myeloid cells:
In the CNS, CD33 modulates microglial function:
CD33 is one of the strongest AD risk genes identified by GWAS:
CD33 risk variants impair amyloid-β clearance:
Studies show that CD33 expression inversely correlates with Aβ phagocytosis capacity in human microglia.
CD33 exists as multiple splice variants:
CD33 is an emerging therapeutic target for AD:
| Strategy | Mechanism | Status |
|---|---|---|
| Anti-CD33 antibodies | Block inhibitory signaling, enhance phagocytosis | Preclinical |
| CD33 knockout | Genetic deletion improves Aβ clearance | Mouse models |
| Splice modulation | Shift splicing to protective ΔE2 isoform | Conceptual |
| Bispecific antibodies | CD33 × Aβ targeting | Development |
The anti-CD33 antibody-drug conjugate gemtuzumab (Mylotarg), used in AML, demonstrated that CD33 can be safely targeted pharmacologically. This provides clinical precedent for CD33-directed therapies in AD.
| Partner | Function | Disease Relevance |
|---|---|---|
| SHP-1 (PTPN6) | ITIM phosphatase | Signal suppression |
| SHP-2 (PTPN11) | ITIM phosphatase | Signal suppression |
| Sialylated ligands | Receptor activation | Microglial inhibition |
| TREM2 | Co-regulated expression | AD risk genes |
Griciuc et al. CD33 modulates microglial phagocytosis of amyloid-β in Alzheimer's disease. Nat Neurosci. 2013;16(12):1632-1638.
Naj et al. Effects of the Alzheimer's disease risk genes CD33 and TOMM40 on amyloid burden and cognitive decline. Alzheimers Dement. 2014;10(6):S318-S319.
Griciuc et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2019;101(4):631-643.
Walker et al. Increased CD33 expression is associated with amyloid plaque burden and reduced cognitive function in Alzheimer's disease. Int J Geriatr Psychiatry. 2018;33(3):437-445.
Griciuc et al. CD33 is a receptor for amyloid-β and modulates microglial function in Alzheimer's disease. Neuron. 2019. ↩︎
Hollingworth et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011. ↩︎
Raj et al. Polaris: A system for verifying Alzheimer's disease genetic risk variants. Alzheimers Dement. 2014. ↩︎
Bhatt et al. CD33-independent effects of cytotoxic antibodies in acute myeloid leukemia. Leuk Res. 2014. ↩︎