CD33 Alzheimer’s risk-altering polymorphism, CD33 expression, and exon 2 splicing
Open accessAbstract
Genome-wide association studies are identifying novel Alzheimer's disease (AD) risk factors. Elucidating the mechanism underlying these polymorphisms is critical to the validation process and, by identifying rate-limiting steps in AD risk, may yield novel therapeutic targets. Here, we elucidate the mechanism of action of the AD-associated polymorphism rs3865444 in the promoter of CD33, a member of the sialic acid-binding Ig-superfamily of lectins (SIGLECs). Immunostaining established that CD33 is expressed in microglia in human brain. Consistent with this finding, CD33 mRNA expression correlated well with expression of the microglial genes CD11b and AIF-1 and was modestly increased with AD status and the rs3865444C AD-risk allele. Analysis of CD33 isoforms identified a common isoform lacking exon 2 (D2-CD33). The proportion of CD33 expressed as D2-CD33 correlated robustly with rs3865444 genotype. Because rs3865444 is in the CD33 promoter region, we sought the functional polymorphism by sequencing CD33 from the promoter through exon 4. We identified a single polymorphism that is coinherited with rs3865444, i.e., rs12459419 in exon 2. Minigene RNA splicing studies in BV2 microglial cells established that rs12459419 is a functional single nucleotide polymorphism (SNP) that modulates exon 2 splicing efficiency. Thus, our primary findings are that CD33 is a microglial mRNA and that rs3865444 is a proxy SNP for rs12459419 that modulates CD33 exon 2 splicing. Exon 2 encodes the CD33 IgV domain that typically mediates sialic acid binding in SIGLEC family members. In summary, these results suggest a novel model wherein SNP-modulated RNA splicing modulates CD33 function and, thereby, AD risk.
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TREM2, CD33, and CD22 play key roles in disease progression in AD patients and neurodegenerative mouse models.
“Most notably, emerging evidence from both AD patients and neurodegenerative mouse models has identified key roles for TREM2, CD33, and CD22 in disease progression (Bemiller et al., 2017; Krasemann et al., 2017; Malik et al., 2013; Pluvinage et al., 2019; Ulland et al., 2017; Wang et al., 2015).”
From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Malik et al., 2013
The Discussion (p. 13324) links CD33 expression and splicing to Alzheimer’s disease risk and describes a proposed role for CD33 and TREM2 in microglial activation. It does not establish a role in disease progression, and this paper provides no evidence about CD22 or progression in neurodegenerative mouse models. (LLM, conf=0.85)
Experimental — accuracy not yet measuredHigher expression of CD33 genes or of CD33 immunolabelled cells was noted in three studies in the superior and middle temporal gyri, frontal cortex and temporal cortex of patients with Alzheimer's disease relative to controls.
“Higher expression of CD33 genes or of CD33 immunolabelled cells was noted in three studies in the superior and middle temporal gyri, frontal cortex and temporal cortex of patients with AD relative to controls.66, 70, 104”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [104]
CD33 expression was shown to correlate with pan-microglial markers Iba1 or CD11b, supporting its microglial localization.
“CD33 expression was shown to correlate with pan-microglial markers Iba1 or CD11b, supporting its microglial localization.66, 70, 104”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [104]
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- Authors
- Malik, M., Simpson, J. F., Parikh, I., Wilfred, B. R., Fardo, D. W., Nelson, P. T., & Estus, S.
- Affiliations
- University of Kentucky (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-08-14
- Volume
- 33
- Issue
- 33
- Pages
- 13320-13325
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3742922
- OpenAlex
- W2150724305
- Cited by
- 262
- References
- 28
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 29 · 2023: 17 · 2022: 23 · 2021: 28 · 2020: 25 · 2019: 20 · 2018: 25 · 2017: 17 · 2016: 18 · 2015: 16 · 2014: 17 · 2013: 3
- FWCI
- 12.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Kentucky
- U.S. Public Health Service (P01-AGO30128)
- National Institute on Aging (P01AG030128, R01AG045775, P30AG028383, K25AG043546)
- National Institute of General Medical Sciences (P20GM103436)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, CD33, alternative splicing, microglia, promoter polymorphism, IgV domain, CD11b, AIF1, genetic risk factors
- MeSH terms
- Alzheimer Disease, Exons, Genotype, Humans, Immunohistochemistry, Promoter Regions, Genetic, Risk Factors, Alternative Splicing, Genetic Predisposition to Disease, Protein Isoforms, Reverse Transcriptase Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Real-Time Polymerase Chain Reaction, Sialic Acid Binding Ig-like Lectin 3
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