CD33 — Cluster of Differentiation 33

CD33 — Cluster of Differentiation 33

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">cd33</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CD33</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Cluster of Differentiation 33</td>
</tr>
<tr>
<td class="label">Alias</td>
<td>Siglec-3</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19q13.41</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>945</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000141548</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P07846</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>159590</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein coding</td>
</tr>
<tr>
<td class="label">RefSeq</td>
<td>NM_001082.5</td>
</tr>
<tr>
<td class="label">Region</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">White matter</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cortex</td>
<td>Medium</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>Low-Medium</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">Anti-CD33 antibodies</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">CD33-blocking antibodies</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="labe

CD33 — Cluster of Differentiation 33

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">cd33</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CD33</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Cluster of Differentiation 33</td>
</tr>
<tr>
<td class="label">Alias</td>
<td>Siglec-3</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19q13.41</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>945</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000141548</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P07846</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>159590</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein coding</td>
</tr>
<tr>
<td class="label">RefSeq</td>
<td>NM_001082.5</td>
</tr>
<tr>
<td class="label">Region</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">White matter</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cortex</td>
<td>Medium</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>Low-Medium</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">Anti-CD33 antibodies</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">CD33-blocking antibodies</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Siglec-engagement blockers</td>
<td>Discovery</td>
</tr>
<tr>
<td class="label">Gene silencing (ASOs)</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Small molecule inhibitors</td>
<td>Discovery</td>
</tr>
<tr>
<td class="label">AD Risk Gene</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">TREM2</td>
<td>Complementary pathways</td>
</tr>
<tr>
<td class="label">PLD3</td>
<td>Microglial function</td>
</tr>
<tr>
<td class="label">ABI3</td>
<td>Wiskott-Aldrich syndrome protein pathway</td>
</tr>
<tr>
<td class="label">INPP5D</td>
<td>ITIM pathway signaling</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>CD33</td>
</tr>
<tr>
<td class="label">Effect on phagocytosis</td>
<td>Inhibitory</td>
</tr>
<tr>
<td class="label">Signaling</td>
<td>ITIM-mediated</td>
</tr>
<tr>
<td class="label">Expression in AD</td>
<td>Increased</td>
</tr>
<tr>
<td class="label">Therapeutic target</td>
<td>Blocking antibody</td>
</tr>
<tr>
<td class="label">Agent Type</td>
<td>Company</td>
</tr>
<tr>
<td class="label">Anti-CD33 mAb (lutetium-177)</td>
<td>Actinium</td>
</tr>
<tr>
<td class="label">CD33-blocking peptide</td>
<td>Academic</td>
</tr>
<tr>
<td class="label">Siglec-Fc decoy</td>
<td>Several</td>
</tr>
<tr>
<td class="label">ASO targeting CD33</td>
<td>Ionis</td>
</tr>
<tr>
<td class="label">Small molecule agonist</td>
<td>Unknown</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>

Pathway Diagram

Overview

CD33 (also known as Siglec-3) is a member of the sialic acid-binding immunoglobulin-type lectin (Siglec) family, encoded by the CD33 gene on chromosome 19q13.41[@crocker2007]. Originally discovered as a surface marker on myeloid cells, CD33 has emerged as one of the most consistently replicated genetic risk factors for late-onset Alzheimer's disease (LOAD) through genome-wide association studies (GWAS)[@naj2011]. As an inhibitory receptor expressed primarily on microglia—the brain's resident immune cells—CD33 plays a critical role in regulating neuroinflammation and phagocytosis, processes central to AD pathogenesis.

The identification of CD33 as an AD risk gene represents a paradigm shift in our understanding of disease mechanisms, highlighting the importance of innate immune dysfunction in neurodegeneration. Unlike many AD risk genes expressed predominantly in neurons, CD33's primary expression on microglia positions it as a key regulator of the brain's immune response.

Gene Information

Gene Structure and Expression

Genomic Organization

The CD33 gene spans approximately 8.3 kb and contains 7 exons. It encodes a type I transmembrane protein with distinct isoforms generated through alternative splicing. The gene is located in a region of chromosome 19 that contains several other immune-related genes, consistent with its role in myeloid cell function.

Chromosomal Position (GRCh38):

• 19q13.41 (51,219,234-51,243,812)
• Sense strand orientation

Protein Structure

CD33 encodes a type I transmembrane protein of 354 amino acids with a molecular weight of approximately 67 kDa:

Domain architecture:

• N-terminal V-type Ig domain: Sialic acid-binding capability with high affinity for α2-6-linked sialic acids
• Two C2-type Ig domains: Receptor structure supporting protein-protein interactions
• Transmembrane domain: Single pass membrane spanning region
• Cytoplasmic tail: Contains 3 ITIM motifs (Immunoreceptor Tyrosine-based Inhibitory Motifs)

Isoform Diversity

Multiple CD33 isoforms exist with distinct functional properties:

• CD33M (Mature isoform): Full-length receptor with intact ITIMs
• CD33m (Mature isoform alternative): Shorter cytoplasmic tail variant
• Soluble CD33 (sCD33): Secreted isoform lacking transmembrane domain

Cellular Expression

Primary Expression:

• Myeloid cells (monocytes, macrophages, microglia)
• Some dendritic cell subsets
• Certain lymphoid populations

• Specifically on microglia, particularly in white matter and perivascular regions
• Low or absent expression on neurons and astrocytes
• Expression increases with aging and in AD brains[@walker2023]

Allen Brain Atlas Data

Gene Expression

• Microglia - Primary expression site, especially in white matter and perivascular regions
• Macrophages - High expression in border-associated populations
• Neurons - Very low to absent
• Astrocytes - Very low to absent

Single-Cell Expression

• Microglia - High expression (one of the highest microglial markers)
• Macrophages - High expression
• Monocytes - High expression
• Other cell types - Minimal expression

Brain Region Expression Levels

External Resources

• [Allen Human Brain Atlas - CD33](https://human.brain-map.org/microarray/search/show?search_term=CD33)
• [Allen Mouse Brain Atlas - CD33](https://mouse.brain-map.org/search/index.html?query=CD33)
• [Allen Cell Type Atlas - CD33](https://celltypes.brain-map.org/)

Molecular Function

Siglec-Mediated Recognition

CD33 recognizes sialic acid residues on glycoproteins and glycolipids through its N-terminal V-type domain. This binding is typically self-recognition (interactions with host sialylated proteins) and functions as an inhibitory "self" signal to prevent inappropriate immune activation[@varki2009].

The sialic acid-binding property is crucial for understanding CD33's function:

• Ligand specificity: Prefers α2-6-linked sialic acids over α2-3-linked
• Self-renewal: Recognizes host glycoproteins as "self"
• Inhibitory signaling: Prevents immune activation against self-tissues

ITIM Signaling

The cytoplasmic tail contains three ITIMs (Immunoreceptor Tyrosine-based Inhibitory Motifs) with the consensus sequence (I/V/L)YXXL/V that recruit phosphatases upon ligand binding:

Signaling cascade:

• SHP-1 (PTPN6): Primary phosphatase recruited, dephosphorylates signaling molecules
• SHP-2 (PTPN11): Secondary phosphatase with dual roles
• PI3K pathway modulation: Alters downstream survival and activation signals

• Inhibition of immune cell activation
• Reduction of cytokine production
• Modulation of phagocytosis
• Promotion of cell survival signals

Microglial Function Regulation

CD33 expressed on microglia regulates multiple critical functions:

Phagocytosis:

• Inhibits clearance of debris and protein aggregates
• Modulates complement-mediated phagocytosis
• Regulates Aβ plaque clearance
• CD33 knockout mice show enhanced Aβ clearance and reduced plaque burden[@gandy2013]

• Suppresses pro-inflammatory responses
• Reduces TNF-α and IL-1β production
• Modulates IL-10 and TGF-β secretion

• Influences microglial viability through PI3K/Akt signaling
• Prevents excessive activation-induced cell death

Role in Alzheimer's Disease

CD33 represents one of the most significant AD risk loci identified through GWAS, with the association replicated across multiple ethnic groups and cohorts.

Genetic Association

GWAS-Identified Variant:

• rs3865444: Primary AD risk variant
• Risk allele: C (protective) vs T (risk)
• Effect size: Odds ratio ~1.10-1.15 per risk allele
• Population: Consistently replicated in European, Asian, and African American cohorts[@coffey2019]
• Mechanism: The risk allele (T) is associated with increased CD33 expression on microglia[@malik2015]

• European ancestry: Consistent replication
• African American: Significant association with modified effect size
• East Asian: Replication in Japanese and Chinese cohorts
• Caribbean Hispanic: Population-specific signals identified

• Interaction with APOE ε4 status
• Modulation by age at disease onset
• Effects on progression rate

Pathogenic Mechanisms

1. Impaired Amyloid Clearance

The primary mechanism by which CD33 contributes to AD:

• Phagocytosis inhibition: Higher CD33 levels inhibit microglial phagocytosis of Aβ plaques
• ITIM signaling: Activated CD33 reduces phagocytic capacity
• Complement modulation: CD33 affects complement receptor-mediated clearance

• CD33 knockout mice: Enhanced Aβ clearance, reduced plaque burden
• CD33 transgenic mice: Increased Aβ accumulation[@gandy2013]
• Human studies: CD33 expression correlates with plaque burden

2. Neuroinflammation Modulation

CD33 risk variants alter neuroinflammatory responses:

• Cytokine dysregulation: Altered production of pro-inflammatory mediators
• Microglial activation: Changed activation states and morphology
• T cell interaction: Modified adaptive immune responses

• Risk variant carriers show distinct cytokine profiles
• CD33 expression correlates with inflammatory markers in CSF
• Brain transcriptomics reveal altered immune pathways

3. Tau Pathology Interaction

While primarily linked to amyloid, CD33 influences tau progression through microglial-mediated mechanisms:

• CD33 genetic variants associated with tauopathy[@schwarting2022]
• Microglial activation influences tau spreading
• Interaction with TREM2 pathways affects tau clearance

4. Interaction with TREM2

CD33 and TREM2 represent complementary AD risk loci:

• Both expressed on microglia
• TREM2 activates phagocytosis; CD33 inhibits it
• Genetic epistasis between loci
• Combined risk effects larger than individual genes

Therapeutic Implications

CD33 represents a promising therapeutic target for AD:

Approved for other use:

• Gemtuzumab ozogamicin: FDA-approved for acute myeloid leukemia (AML)
• Provides proof-of-concept for anti-CD33 therapy

• Systemic delivery to brain microglia
• Potential effects on peripheral immune cells
• Balancing inflammatory versus anti-inflammatory functions
• Timing of intervention (early vs. late disease)[@song2020]

Interaction with Other AD Risk Genes

CD33 does not function in isolation but interacts with multiple AD risk genes:

Clinical Relevance

Genetic Testing

• CD33 risk variants are included in some multi-gene AD risk panels
• Current clinical utility is limited due to small effect size
• Not recommended for standalone predictive testing
• Useful in polygenic risk scores

Biomarker Potential

Fluid Biomarkers:

• CD33 expression on peripheral monocytes correlates with brain expression
• Soluble CD33 (sCD33) being investigated as disease marker
• CSF CD33 levels associated with disease status

• PET imaging ligands targeting CD33 in development
• Microglial activation imaging correlates with CD33 expression

• Risk stratification
• Disease progression monitoring
• Therapeutic targeting

Research Directions

Key Questions

Ongoing Studies

• Human brain studies: Single-cell analysis of CD33-expressing microglia[@chen2023]
• Animal models: Anti-CD33 antibody testing in mouse models
• Biomarker studies: sCD33 as diagnostic marker
• Clinical trials: Planning for first-in-human studies

Recent Advances

• Metabolic modulation: CD33 affects microglial metabolism in AD[@yang2024]
• Therapeutic efficacy: Anti-CD33 therapy reduces amyloid and tau in models[@zhao2024]
• Cognitive outcomes: CD33 genetic variants influence cognitive decline[@kraus2023]
• Innate immunity: Broader role of CD33 in neuroinflammation[@tanzi2023]

Animal Models

Mouse Models

• CD33 knockout: Viable, enhanced phagocytosis
• CD33 transgenic: Increased Aβ accumulation
• APP/PS1 crosses: Exacerbated pathology with CD33
• Humanized models: Expressing human CD33 isoforms

In Vitro Models

• Primary microglial cultures: Knockdown/overexpression studies
• iPSC-derived microglia: Human model systems
• Organotypic cultures: Brain slice models

Key Publications

Cross-Linking and Related Content

Related Genes and Proteins

• [TREM2 Gene](/genes/trem2) — Complementing AD risk gene
• [APP Gene](/proteins/app) — Amyloid precursor protein
• [APOE Gene](/genes/apoe) — Major AD risk gene
• [PLD3 Gene](/genes/pld3) — Microglial function in AD
• [BIN1 Gene](/genes/bin1) — AD risk gene

Related Diseases

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• [Amyotrophic Lateral Sclerosis](/diseases/als)

Related Mechanisms

• [Microglial Activation](/mechanisms/microglial-activation)
• [Neuroinflammation](/mechanisms/neuroinflammation)
• [Amyloid Clearance](/mechanisms/amyloid-clearance)
• [Innate Immune Response](/mechanisms/innate-immune-response)
• [Phagocytosis](/mechanisms/phagocytosis)

Cell Types

• [Microglia](/cell-types/microglia-neuroinflammation)
• [Monocytes](/cell-types/monocytes)
• [Macrophages](/cell-types/macrophages)

External Links

• [NCBI Gene: CD33](https://www.ncbi.nlm.nih.gov/gene/945)
• [UniProt: P07846](https://www.uniprot.org/uniprot/P07846)
• [Ensembl: ENSG00000141548](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000141548)
• [GWAS Catalog: CD33](https://www.ebi.ac.uk/gwas/variants/rs3865444)
• [Human Protein Atlas: CD33](https://www.proteinatlas.org/ENSG00000141548-CD33)
• [Allen Brain Atlas: CD33](https://human.brain-map.org/microarray/search/show?search_term=CD33)
• [GeneCards: CD33](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CD33)

Summary

CD33 (Siglec-3) is a critical AD risk gene encoding an inhibitory receptor on microglia. The GWAS-identified variant rs3865444 is associated with increased CD33 expression and reduced amyloid clearance. CD33 regulates microglial phagocytosis through ITIM-mediated signaling, representing a key link between innate immune dysfunction and AD pathogenesis. Therapeutic targeting of CD33 offers promise for disease modification, though challenges remain in achieving adequate brain delivery and maintaining immune homeostasis.

Structural Biology

Protein Domain Architecture

CD33 possesses a distinctive structural organization that underlies its function as an inhibitory receptor:

V-Type Ig Domain (N-terminal):

• Comprises residues 1-110
• Contains the sialic acid-binding site
• Conserved across Siglec family members
• Forms a β-sandwich fold typical of Ig superfamily
• Binding pocket has specificity for α2-6-linked sialic acids

• Two C2-type domains (residues 111-250)
• Support the overall receptor structure
• Provide flexibility for ligand interaction
• Contain conserved disulfide bonds for stability

• Single pass transmembrane helix (residues 260-290)
• Contains a conserved cysteine for dimerization
• Anchors receptor in plasma membrane
• Contains positively charged residues for basolateral targeting

• Contains three ITIM motifs (residues 300-354)
• YXXL/V consensus sequences
• Multiple serine and threonine residues for phosphorylation
• C-terminal tail interacts with phosphatases

Structural Insights from Cryo-EM

Recent structural studies have provided detailed insights:

• Full-length CD33 structure resolved to 3.2 Å
• ITIM domains adopt extended confirmation
• Dimerization interface identified
• Sialic acid binding pocket well-defined
• Drug binding sites characterized

Signaling Pathways

Downstream Effectors

SHP-1 (PTPN6):

• Primary ITIM phosphatase
• Deactivates Syk family kinases
• Reduces calcium signaling
• Inhibits respiratory burst
• Modulates cytokine transcription

• Dual-specificity phosphatase
• Can have both positive and negative effects
• Modulates PI3K/Akt pathway
• Affects cell survival signals

• Activated when ITIMs are not phosphorylated
• Promotes phagocytosis and activation
• CD33 inhibits Syk to reduce microglial activation

Cross-Talk with TREM2

The CD33-TREM2 axis represents a critical balance in microglial function:

Key interactions:

• Both regulate complement-mediated phagocytosis
• Compete for downstream signaling effectors
• Genetic epistasis affects AD risk
• Combined targeting may have synergistic effects

Metabolic Regulation

CD33 and Microglial Metabolism

Recent research has revealed CD33's role in microglial metabolic reprogramming:

Glycolysis Regulation:

• CD33 signaling reduces glycolytic rate
• Affects ATP production in microglia
• Modulates inflammatory response through metabolism
• CD33 deletion increases glycolytic capacity

• ITIM signaling affects mitochondrial membrane potential
• Alters reactive oxygen species production
• Impacts cell survival under stress
• Metabolic changes affect antigen presentation

• Metabolic dysfunction is a hallmark of AD microglia
• CD33-mediated metabolic suppression may contribute to disease
• Metabolic modulators as potential therapeutics
• CD33 effects on metabolism compound with aging

Clinical Development

Therapeutic Agents in Pipeline

Clinical Trial Design Considerations

Patient Selection:

• Genotype stratification for rs3865444
• APOE ε4 status consideration
• Disease stage optimization
• Biomarker-positive subjects

• CSF Aβ and tau levels
• PET imaging for plaques and tangles
• Cognitive measures (ADAS-Cog, CDR)
• Microglial activation markers (PET)

• Peripheral immune suppression
• Infection risk assessment
• Off-target effects on monocytes
• Long-term safety monitoring

Genetics and Population Studies

Meta-Analyses

Large-scale meta-analyses have consolidated CD33's role in AD:

IGAP Consortium:

• 74,046 AD cases and 356,914 controls
• Genome-wide significance confirmed
• Effect size consistent across cohorts
• Multiple independent signals identified

• Smaller effect size than European ancestry
• Different linkage disequilibrium structure
• Population-specific variants under investigation

• Replication in Japanese and Chinese cohorts
• Similar effect direction and magnitude
• Shared causal variant likely

Rare Variants

Whole-exome sequencing has identified rare CD33 variants:

• Missense variants in coding region
• Effects on protein function under investigation
• Potential for loss-of-function interpretation
• May explain missing heritability

Animal Model Insights

Transgenic Models

CD33 Knockout Mouse:

• Viable and fertile
• Enhanced microglial phagocytosis
• Reduced amyloid plaque burden
• Improved cognitive performance
• Compensatory upregulation of related proteins

• Expression pattern matches human microglia
• Increased Aβ accumulation
• Altered microglial morphology
• Validates therapeutic targeting

• Synergistic effect on plaque load
• Accelerated cognitive decline
• Enhanced neuroinflammation
• Supports combination targeting

Behavioral Studies

• Morris water maze: CD33 deletion improves learning
• Y-maze: Enhanced spatial memory
• Elevated plus maze: No anxiety changes
• Rotarod: No motor deficits
• Social interaction: Normal behavior

Outstanding Questions

Key Research Gaps

Future Research Directions

• Single-cell RNA-seq of CD33-expressing microglia
• Time-series proteomics during disease progression
• Human brain organoid models with CD33 variants
• CRISPR-based gene editing approaches
• Novel imaging agents for CD33 visualization

Pathway Diagram

The following diagram shows the key molecular relationships involving CD33 — Cluster of Differentiation 33 discovered through SciDEX knowledge graph analysis: