CD33 (Siglec-3)

Pathway Diagram

flowchart TD
    CD33["CD33"]
    style CD33 fill:#006494,stroke:#4fc3f7,stroke-width:3px,color:#e0e0e0
    Microglial_Phagocytosis_of_Amy["Microglial Phagocytosis of Amyloid-beta"]
    CD33 -->|"involved in"| Microglial_Phagocytosis_of_Amy
    Alzheimer_s_disease["Alzheimer's disease"]
    CD33 -->|"biomarker for"| Alzheimer_s_disease
    Alzheimer["Alzheimer"]
    CD33 -->|"associated with"| Alzheimer
    Als["Als"]
    CD33 -->|"therapeutic target"| Als
    CD33 -->|"activates"| Als
    Leukemia["Leukemia"]
    CD33 -->|"therapeutic target"| Leukemia
    CD33 -->|"regulates"| Alzheimer
    MICROGLIA["MICROGLIA"]
    CD33 -->|"associated with"| MICROGLIA
    ALZHEIMER_S_DISEASE["ALZHEIMER'S DISEASE"]
    ALZHEIMER_S_DISEASE -->|"associated with"| CD33
    AMYLOID["AMYLOID"]
    AMYLOID -->|"associated with"| CD33
    APOE["APOE"]
    APOE -->|"associated with"| CD33
    TREM2["TREM2"]
    TREM2 -->|"associated with"| CD33
    MICROGLIA -->|"associated with"| CD33
    APP["APP"]
    APP -->|"associated with"| CD33
    NEURODEGENERATION["NEURODEGENERATION"]
    NEURODEGENERATION -->|"associated with"| CD33
    TREM2 -->|"regulates"| CD33
    style Microglial_Phagocytosis_of_Amy fill:#888,stroke:#4fc3f7,color:#e0e0e0
    style Alzheimer_s_disease fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0
    style Alzheimer fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0
    style Als fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0
    style Leukemia fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0
    style MICROGLIA fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0
    style ALZHEIMER_S_DISEASE fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0
    style AMYLOID fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0
    style APOE fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0
    style TREM2 fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0
    style APP fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0
    style NEURODEGENERATION fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0

Overview

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.

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:

1. Sialic acid binding: Recognizes α2,6-linked sialic acids on glycoproteins

2. ITIM phosphorylation: Ligand binding triggers Src-family kinase phosphorylation

3. Phosphatase recruitment: SHP-1/SHP-2 bind phosphorylated ITIMs

4. Signal suppression: Phosphatases dephosphorylate activation pathways

Microglial Regulation

In the CNS, CD33 modulates microglial function:

• Phagocytosis inhibition: CD33 signaling suppresses microglial phagocytosis^{1CD33 is a receptor for amyloid-β and modulates microglial function in Alzheimer's disease2019 · Neuron · PMID 30679567Open reference}

• 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^{2Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease2011 · Nat Genet · DOI 10.1038/ng.803Open reference}

• Effect size: OR ~1.15-1.20 for late-onset AD

• Expression correlation: Risk alleles increase full-length CD33 in microglia^{3Polaris: A system for verifying Alzheimer's disease genetic risk variants2014 · Alzheimers Dement · PMID 25239853Open reference}

Pathogenic Mechanism

CD33 risk variants impair amyloid-β clearance:

1. Increased CD33 expression: Risk alleles elevate CD33 protein levels

2. Enhanced ITIM signaling: Stronger microglial inhibition

3. Reduced phagocytosis: Impaired Aβ uptake and clearance

4. Plaque accumulation: Accelerated amyloid pathology^{4CD33-independent effects of cytotoxic antibodies in acute myeloid leukemia2014 · Leuk Res · DOI 10.1016/j.leukres.2014.03.012Open reference}

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:

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

Key Publications

1. Griciuc et al. CD33 modulates microglial phagocytosis of amyloid-β in Alzheimer’s disease. Nat Neurosci. 2013;16(12):1632-1638.

2. 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.

3. Griciuc et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2019;101(4):631-643.

4. 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.

See Also

• CD33 Gene

External Links

• UniProt: P20138

• PDB structures

• GeneCards: CD33