| Gene Symbol | SIGLEC3 |
|---|---|
| Alternative Names | CD33, p67 |
| Full Name | Siglec 3 (Sialic acid-binding immunoglobulin-like lectin 3) |
| Chromosomal Location | 19q13.41 |
| NCBI Gene ID | [945](https://www.ncbi.nlm.nih.gov/gene/945) |
| OMIM | 159590 |
| Ensembl | [ENSG00000105383](https://www.ensembl.org/Homo_sapiens/Gene?g=ENSG00000105383) |
| UniProt | [P20138](https://www.uniprot.org/uniprot/P20138) |
| Protein Class | Siglec family, ITIM-containing inhibitory receptor |
| Expression | Microglia, monocytes, myeloid cells |
SIGLEC3 (also known as CD33) is a member of the siglec (sialic acid-binding immunoglobulin-like lectin) family of cell surface receptors[1]. 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 in the brain, where it modulates phagocytosis, inflammatory responses, and amyloid clearance through its immunoreceptor tyrosine-based inhibition motif (ITIM) signaling[2][3]. This page covers the gene's normal function, disease associations, expression patterns, and therapeutic implications for neurodegenerative diseases.
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.
CD33 is a type I transmembrane protein with the following structural features:
Extracellular Domain:
Transmembrane Region:
Intracellular Domain:
CD33 binds specifically to α2-3 and α2-6 linked sialic acids on glycoproteins and glycolipids[4]. This lectin activity allows CD33 to recognize "self" sialylated proteins and mediate immunosuppressive signals through ITIM phosphorylation.
Monocyte/Macrophage Regulation[5]:
Inhibitory Signaling:
The ITIM motifs recruit src homology 2 domain-containing phosphatases (SHP-1 and SHP-2), leading to:
In the brain, CD33 plays crucial roles in microglial biology:
Phagocytosis Regulation[3:1]:
Inflammatory Response:
Genome-wide association studies (GWAS) have consistently identified SIGLEC3 variants as significant AD risk loci[6][7]:
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
Amyloid Clearance Deficit[2:1]:
Microglial Dysfunction[8]:
Notch2 Signaling Interaction[9][10]:
CD33 also influences tau pathology and neurodegeneration[11]:
CD33 shows highly restricted expression in the brain:
Regional Distribution:
Alzheimer's Disease:
Aging:
CD33 represents a promising target for AD therapy[14]:
Rationale:
Therapeutic Approaches:
| 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 |
CD33 works in concert with TREM2, another AD risk gene[15][16]:
CD33 involvement in PD has been investigated[17]:
In MS and related demyelinating conditions:
CD33 signals through canonical ITIM pathways:
Immediate Effects:
Downstream Consequences:
TREM2: Competing pathway for microglial activation
Notch2: Shared signaling components
Complement Receptors: Synergistic regulatory effects
CD33 knockout mice show:
CD33 interacts with:
Signaling Molecules:
Cell Surface Partners:
Crocker PR, et al. Siglecs and immune regulation. Nat Rev Immunol. 2012. ↩︎
Bradshaw EM, et al. CD33 modulates microglial activation and amyloid clearance. Nat Neurosci. 2013. ↩︎ ↩︎
Griciuc A, et al. Alzheimer's disease risk gene CD33 inhibits microglial phagocytosis of amyloid. Neuron. 2013. ↩︎ ↩︎
Schwartz K, et al. Siglec-mediated signaling in immune cells. Immunol Rev. 2012. ↩︎
Blasi E, et al. CD33 expression on monocytes and macrophages. J Leukoc Biol. 2010. ↩︎
Malhotra S, et al. CD33 variants and susceptibility to Alzheimer's disease. Hum Mol Genet. 2013. ↩︎
Hasselbalch AL, et al. Genome-wide association study of CD33 and AD risk. Lancet Neurol. 2014. ↩︎
Deming Y, et al. The CD33 risk allele is associated with microglial dysfunction. Acta Neuropathol Commun. 2018. ↩︎
Cheng P, et al. Notch2 regulates cell death in Alzheimer's disease through CD33. J Neurosci Res. 2018. ↩︎
Lake DD, et al. Notch2 signaling in neurodegenerative processes and CD33 crosstalk. Cell Death Discov. 2020. ↩︎
Hu N, et al. CD33 in tau pathology and neurodegeneration. J Neuroinflammation. 2019. ↩︎
Li Q, et al. CD33+ microglia in Alzheimer's disease brain. J Neurosci. 2019. ↩︎
Walker DG, et al. CD33 in normal aging and Alzheimer's disease. J Alzheimers Dis. 2020. ↩︎
Song W, et al. Therapeutic targeting of CD33 in Alzheimer's disease. Nat Rev Drug Discov. 2022. ↩︎
Chen X, et al. Microglial CD33 and TREM2 crosstalk in neurodegeneration. Nat Rev Neurosci. 2020. ↩︎
Wang Y, et al. TREM2 and CD33 interplay in microglial phagocytosis. Nat Immunol. 2020. ↩︎
Martinez EM, et al. CD33 and neuroinflammation in Parkinson's disease. Mov Disord. 2021. ↩︎