CD33 (Siglec-3)
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<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
Mermaid diagram (expand to render)
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
The extracellular domains mediate binding to sialylated glycoproteins and gangliosides, while ITIM signaling recruits SHP-1 and SHP-2 phosphatases to inhibit cellular activation.
Normal Function
Immune Inhibition
CD33 functions as an inhibitory receptor on myeloid cells:
Sialic acid binding: Recognizes α2,6-linked sialic acids on glycoproteins
ITIM phosphorylation: Ligand binding triggers Src-family kinase phosphorylation
Phosphatase recruitment: SHP-1/SHP-2 bind phosphorylated ITIMs
Signal suppression: Phosphatases dephosphorylate activation pathwaysMicroglial 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:
Increased CD33 expression: Risk alleles elevate CD33 protein levels
Enhanced ITIM signaling: Stronger microglial inhibition
Reduced phagocytosis: Impaired [Aβ](/proteins/amyloid-beta) uptake and clearance
Plaque accumulation: Accelerated amyloid pathology[@bhatt2014]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
Griciuc et al. [CD33 modulates microglial phagocytosis of amyloid-β in Alzheimer's disease](https://doi.org/10.1038/nn.3622). 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](https://pubmed.ncbi.nlm.nih.gov/25239853/). Alzheimers Dement. 2014;10(6):S318-S319.
Griciuc et al. [Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta](https://pubmed.ncbi.nlm.nih.gov/30679567/). 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](https://doi.org/10.1002/gps.4930). Int J Geriatr Psychiatry. 2018;33(3):437-445.See Also
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
[Griciuc et al, CD33 is a receptor for amyloid-β and modulates microglial function in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30679567/)
[Hollingworth et al, Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease (2011)](https://doi.org/10.1038/ng.803)
[Raj et al, Polaris: A system for verifying Alzheimer's disease genetic risk variants (2014)](https://pubmed.ncbi.nlm.nih.gov/25239853/)
[Bhatt et al, CD33-independent effects of cytotoxic antibodies in acute myeloid leukemia (2014)](https://doi.org/10.1016/j.leukres.2014.03.012)Pathway Diagram
The following diagram shows the key molecular relationships involving CD33 (Siglec-3) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)