SIGLEC3 Gene (CD33)

SIGLEC3 Gene (CD33)

<div class="infobox infobox-gene">
<h3>SIGLEC3 (CD33)</h3>
<table>
<tr><th>Gene Symbol</th><td>SIGLEC3</td></tr>
<tr><th>Alternative Names</th><td>CD33, p67</td></tr>
<tr><th>Full Name</th><td>Siglec 3 (Sialic acid-binding immunoglobulin-like lectin 3)</td></tr>
<tr><th>Chromosomal Location</th><td>19q13.41</td></tr>
<tr><th>NCBI Gene ID</th><td>[945](https://www.ncbi.nlm.nih.gov/gene/945)</td></tr>
<tr><th>OMIM</th><td>159590</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000105383](https://www.ensembl.org/Homo_sapiens/Gene?g=ENSG00000105383)</td></tr>
<tr><th>UniProt</th><td>[P20138](https://www.uniprot.org/uniprot/P20138)</td></tr>
<tr><th>Protein Class</th><td>Siglec family, ITIM-containing inhibitory receptor</td></tr>
<tr><th>Expression</th><td>Microglia, monocytes, myeloid cells</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

SIGLEC3 (also known as CD33) is a member of the siglec (sialic acid-binding immunoglobulin-like lectin) family of cell surface receptors[@crocker2012]. Originally characterized on monocytes and macrophages, CD33 is now recognized as a critical regulator of microglial function in the central nervous system. Genetic variants in the SIGLEC3 gene have been consistently associated with Alzheimer's disease (AD) risk, making it one of the most significant immune-related genetic determinants of neurodegeneration.

SIGLEC3 Gene (CD33)

<div class="infobox infobox-gene">
<h3>SIGLEC3 (CD33)</h3>
<table>
<tr><th>Gene Symbol</th><td>SIGLEC3</td></tr>
<tr><th>Alternative Names</th><td>CD33, p67</td></tr>
<tr><th>Full Name</th><td>Siglec 3 (Sialic acid-binding immunoglobulin-like lectin 3)</td></tr>
<tr><th>Chromosomal Location</th><td>19q13.41</td></tr>
<tr><th>NCBI Gene ID</th><td>[945](https://www.ncbi.nlm.nih.gov/gene/945)</td></tr>
<tr><th>OMIM</th><td>159590</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000105383](https://www.ensembl.org/Homo_sapiens/Gene?g=ENSG00000105383)</td></tr>
<tr><th>UniProt</th><td>[P20138](https://www.uniprot.org/uniprot/P20138)</td></tr>
<tr><th>Protein Class</th><td>Siglec family, ITIM-containing inhibitory receptor</td></tr>
<tr><th>Expression</th><td>Microglia, monocytes, myeloid cells</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

SIGLEC3 (also known as CD33) is a member of the siglec (sialic acid-binding immunoglobulin-like lectin) family of cell surface receptors[@crocker2012]. Originally characterized on monocytes and macrophages, CD33 is now recognized as a critical regulator of microglial function in the central nervous system. Genetic variants in the SIGLEC3 gene have been consistently associated with Alzheimer's disease (AD) risk, making it one of the most significant immune-related genetic determinants of neurodegeneration.

CD33 is expressed primarily on [microglia](/cell-types/microglia-neuroinflammation) in the brain, where it modulates phagocytosis, inflammatory responses, and amyloid clearance through its immunoreceptor tyrosine-based inhibition motif (ITIM) signaling[@bradshaw2013][@griciuc2013]. This page covers the gene's normal function, disease associations, expression patterns, and therapeutic implications for neurodegenerative diseases.

Gene Structure and Protein Biology

Gene Organization

The SIGLEC3 gene is located on chromosome 19q13.41 and consists of 7 exons encoding a 382-amino acid transmembrane protein. The gene spans approximately 15 kb and exhibits typical housekeeping gene structure with a CpG-rich promoter region.

Protein Structure

CD33 is a type I transmembrane protein with the following structural features:

Extracellular Domain:

• One V-type immunoglobulin-like domain that binds sialic acids
• Two C2-type Ig-like domains
• N-terminal sialic acid-binding site (sialoside-binding pocket)
• Variable region determining ligand specificity

• Single-pass transmembrane helix
• Conserved residues for signal transduction

• Three ITIMs (Immunoreceptor Tyrosine-based Inhibition Motifs)
• One ITIM-like motif
• Phosphatase recruitment sites (SHP-1, SHP-2)

Sialic Acid Recognition

CD33 binds specifically to α2-3 and α2-6 linked sialic acids on glycoproteins and glycolipids[@schwartz2012]. This lectin activity allows CD33 to recognize "self" sialylated proteins and mediate immunosuppressive signals through ITIM phosphorylation.

Normal Biological Functions

Immune Cell Function

Monocyte/Macrophage Regulation[@blasi2010]:

• Inhibits activation of myeloid cells
• Modulates cytokine production
• Regulates phagocytic activity
• Prevents excessive inflammation

• Inhibition of actin cytoskeleton reorganization
• Suppression of respiratory burst
• Reduced cytokine transcription
• Decreased antigen presentation

Microglial Modulation

In the brain, CD33 plays crucial roles in microglial biology:

Phagocytosis Regulation[@griciuc2013]:

• Inhibits uptake of complement-opsonized particles
• Modulates pattern recognition receptor signaling
• Regulates debris clearance

• Dampens microglial activation
• Reduces production of pro-inflammatory cytokines
• Promotes anti-inflammatory phenotype
• Prevents excessive neuroinflammation

Role in Alzheimer's Disease

Genetic Association

Genome-wide association studies (GWAS) have consistently identified SIGLEC3 variants as significant AD risk loci[@malhotra2013][@hasselbalch2014]:

Risk Allele: rs3865444^C (non-coding variant) Effect: Increased AD risk (~1.1-1.2 odds ratio per risk allele) Population: Multiple ancestry groups validated Mechanism: Altered CD33 expression and function

Mechanisms in AD Pathogenesis

Amyloid Clearance Deficit[@bradshaw2013]:

• CD33 risk allele associated with reduced amyloid clearance
• Increased CD33 expression in AD microglia
• ITIM signaling inhibits phagocytosis
• Overexpression leads to amyloid accumulation

• CD33+ microglia show altered morphology
• Reduced process extension toward amyloid plaques
• Impaired surveillance behavior
• Defective antigen presentation

• CD33 interacts with Notch2 signaling
• Crosstalk modulates cell death pathways
• Influences neuronal survival in AD

Tau Pathology Connection

CD33 also influences tau pathology and neurodegeneration[@hu2019]:

• CD33 expression correlates with tau burden
• Modulates microglial response to tau
• Affects spread of tau pathology

Expression Pattern

Cell-Type Specificity

CD33 shows highly restricted expression in the brain:

Primary Expression[@li2019][@walker2020]:

• Microglia (especially in white matter)
• Perivascular macrophages
• Limited expression on other CNS cells

• Highest in white matter tracts
• Moderate in cortical gray matter
• Lower in hippocampus
• Variable across brain regions

Alterations in Disease

Alzheimer's Disease:

• Increased CD33+ microglial density in AD brain
• Upregulation in prodromal and established AD
• Correlation with amyloid plaque burden
• Association with cognitive decline

• Age-related increase in CD33 expression
• Contributes to immunosenescence
• May predispose to neurodegenerative processes

Therapeutic Implications

CD33 as Therapeutic Target

CD33 represents a promising target for AD therapy[@song2022]:

Rationale:

• Genetic validation from GWAS
• Modifiable by pharmacological intervention
• Accessible target on microglia

| Strategy | Approach | Status |
|----------|----------|--------|
| Antibody-based | Anti-CD33 monoclonal antibodies | Preclinical |
| Small molecule | CD33 antagonists/inverse agonists | Early research |
| Gene therapy | siRNA against CD33 | Preclinical |
| Immunomodulation | TREM2-CD33 balance modulators | Early research |

TREM2 Interplay

CD33 works in concert with TREM2, another AD risk gene[@chen2020][@wang2020]:

• TREM2 promotes microglial phagocytosis
• CD33 inhibits phagocytosis
• Therapeutic strategies may need to address both
• Balance determines net microglial activity

Role in Other Neurological Diseases

Parkinson's Disease

CD33 involvement in PD has been investigated[@martinez2021]:

• CD33+ microglia in substantia nigra
• Potential modulation of dopaminergic neuron survival
• Possible role in neuroinflammation

Multiple Sclerosis

In MS and related demyelinating conditions:

• CD33 on microglia and infiltrating monocytes
• May modulate lesion activity
• Potential for disease modification

Other Neurodegenerative Conditions

• Amyotrophic lateral sclerosis (ALS)
• Frontotemporal dementia
• Huntington's disease
• Less characterized than in AD

Signaling Pathways

ITIM-Mediated Inhibition

CD33 signals through canonical ITIM pathways:

Immediate Effects:

• SHP-1/SHP-2 recruitment
• Dephosphorylation of activation signals
• Inhibition of PI3K signaling
• Reduced calcium mobilization

• Suppressed inflammatory gene expression
• Reduced reactive oxygen species
• Decreased phagocytic activity
• Altered antigen presentation

Cross-Talk with Other Receptors

TREM2: Competing pathway for microglial activation Notch2: Shared signaling components Complement Receptors: Synergistic regulatory effects

Animal Models

Mouse Models

CD33 knockout mice show:

• Increased microglial phagocytosis
• Enhanced amyloid clearance
• Reduced plaque burden in AD models
• Normal development and behavior

Limitations

• Species differences in sialic acid biology
• Mouse CD33 not orthologous to human CD33
• Need for humanized models

Research Methods

Genetic Studies

• GWAS meta-analysis
• Fine-mapping of risk loci
• eQTL analysis
• Exome sequencing

Molecular Biology

• qPCR for expression analysis
• Western blotting
• Flow cytometry
• Immunohistochemistry

Functional Studies

• Phagocytosis assays
• Cytokine profiling
• Calcium imaging
• Live cell imaging

Clinical Translation

• Biomarker development
• PET imaging ligands
• CSF CD33 measurement

Interaction Network

Protein Interactions

CD33 interacts with:

Signaling Molecules:

• SHP-1 (PTPN6)
• SHP-2 (PTPN11)
• Grb2
• p85 subunit of PI3K

• Siglec ligands (glycoproteins)
• TREM2
• Complement receptors
• MHC molecules

Pathway Participation

• Immunoreceptor signaling
• Phagocytosis regulation
• Cytokine signaling
• Cell adhesion

Cross-Linking to Related Mechanisms

Related Neurodegenerative Concepts

• [Alzheimer's Disease](/diseases/alzheimers-disease) — Primary disease association
• [Parkinson's Disease](/diseases/parkinsons-disease) — Related neuroinflammation
• [Microglia](/cell-types/microglia-neuroinflammation) — Primary expressing cell
• [Amyloid Clearance](/mechanisms/amyloid-clearance) — Key physiological function
• [Neuroinflammation](/mechanisms/neuroinflammation) — Modulated pathway

Related Genes

• [TREM2](/genes/trem2) — AD risk gene, interacts with CD33
• [MS4A6A](/genes/ms4a6a) — AD risk gene, co-regulated
• [PLCG2](/genes/plcg2) — AD risk gene, microglial signaling

Future Directions

Key Research Questions

Emerging Approaches

• CD33-specific antibodies
• Small molecule inhibitors
• Gene editing approaches
• Cell-type specific delivery

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Microglia](/cell-types/microglia-neuroinflammation)
• [Neuroinflammation](/mechanisms/neuroinflammation)
• [TREM2](/genes/trem2)
• [Amyloid Plaques](/mechanisms/amyloid-plaques)
• [Microglial Activation](/mechanisms/microglial-activation)

External Links

• [NCBI Gene: SIGLEC3 (945)](https://www.ncbi.nlm.nih.gov/gene/945)
• [UniProt: P20138](https://www.uniprot.org/uniprot/P20138)
• [OMIM: 159590](https://www.omim.org/entry/159590)
• [Ensembl: ENSG00000105383](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000105383)
• [ClinVar: SIGLEC3 variants](https://www.ncbi.nlm.nih.gov/clinvar/?term=SIGLEC3)

References