CD33 (Siglec-3)

CD33 (Siglec-3)

<div class="infobox" style="float:right; width:280px; padding:10px; border:1px solid #ddd; margin:0 0 10px 10px; background:#f9f9f9;">
<h3 style="margin-top:0; border-bottom:1px solid #ccc;">CD33</h3>
<table style="width:100%; font-size:0.9em;">
<tr><td><b>Gene</b></td><td>[CD33](/genes/cd33)</td></tr>
<tr><td><b>UniProt</b></td><td>[P20138](https://www.uniprot.org/uniprot/P20138)</td></tr>
<tr><td><b>MW</b></td><td>40 kDa (unglycosylated)</td></tr>
<tr><td><b>Location</b></td><td>Cell membrane (microglia, myeloid cells)</td></tr>
<tr><td><b>PDB</b></td><td>[5J06](https://www.rcsb.org/structure/5J06)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">251 edges</a></td>
</tr>
</table>
</div>

Pathway Diagram

CD33 (Siglec-3)

<div class="infobox" style="float:right; width:280px; padding:10px; border:1px solid #ddd; margin:0 0 10px 10px; background:#f9f9f9;">
<h3 style="margin-top:0; border-bottom:1px solid #ccc;">CD33</h3>
<table style="width:100%; font-size:0.9em;">
<tr><td><b>Gene</b></td><td>[CD33](/genes/cd33)</td></tr>
<tr><td><b>UniProt</b></td><td>[P20138](https://www.uniprot.org/uniprot/P20138)</td></tr>
<tr><td><b>MW</b></td><td>40 kDa (unglycosylated)</td></tr>
<tr><td><b>Location</b></td><td>Cell membrane (microglia, myeloid cells)</td></tr>
<tr><td><b>PDB</b></td><td>[5J06](https://www.rcsb.org/structure/5J06)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">251 edges</a></td>
</tr>
</table>
</div>

Pathway Diagram

Overview

CD33 (Siglec-3) is a sialic acid-binding immunoglobulin-like lectin expressed primarily on [microglia](/cell-types/microglia-neuroinflammation) 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.

Structure and Domains

CD33 is a type I transmembrane protein:

• V-set Ig domain: Extracellular N-terminal domain for sialic acid binding
• C2-set Ig domain: Second extracellular domain
• Transmembrane domain: Single-pass membrane anchor
• Cytoplasmic ITIMs: Two immunoreceptor tyrosine-based inhibitory motifs

Normal Function

Immune Inhibition

CD33 functions as an inhibitory receptor on myeloid cells:

Microglial Regulation

In the CNS, CD33 modulates microglial function:

• Phagocytosis inhibition: CD33 signaling suppresses microglial phagocytosis[@griciuc2019]
• Cytokine production: Inhibits pro-inflammatory cytokine release
• Tolerance maintenance: Prevents excessive microglial activation

Role in Alzheimer's Disease

Genetic Risk Factor

CD33 is one of the strongest AD risk genes identified by GWAS:

• Risk allele: The rs3865444 risk allele correlates with increased CD33 expression[@hollingworth2011]
• Effect size: OR ~1.15-1.20 for late-onset AD
• Expression correlation: Risk alleles increase full-length CD33 in microglia[@raj2014]

Pathogenic Mechanism

CD33 risk variants impair amyloid-β clearance:

Studies show that CD33 expression inversely correlates with Aβ phagocytosis capacity in human microglia.

Transcript Variants

CD33 exists as multiple splice variants:

• Full-length (FL-CD33): Contains both V-set and C2-set domains, risk-associated
• Truncated (ΔE2-CD33): Lacks the sialic acid-binding domain, potentially protective
• Splicing regulation: AD risk variants favor FL-CD33 production

Therapeutic Targeting

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 |

Gemtuzumab Ozogamicin Insight

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.

Other Disease Associations

Multiple Sclerosis

• Protective allele: Some CD33 variants may reduce MS risk
• Microglial modulation: CD33 influences inflammatory responses in MS lesions

Cancer

• Acute myeloid leukemia: CD33 is a therapeutic target (gemtuzumab)
• Tumor-associated macrophages: CD33+ suppressive myeloid cells infiltrate tumors

Protein Interactions

| 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](/proteins/trem2) | Co-regulated expression | AD risk genes |

Key Publications

See Also

• [CD33 Gene](/genes/cd33)

External Links

• [UniProt: P20138](https://www.uniprot.org/uniprot/P20138)
• [PDB structures](https://www.rcsb.org/search?q=uniprot:P20138)
• [GeneCards: CD33](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CD33)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving CD33 (Siglec-3) discovered through SciDEX knowledge graph analysis: