CD33 Alzheimer's risk-altering polymorphism, CD33 expression, and exon 2 splicing

Manasi Malik, James F. Simpson, Ishita Parikh, Bernard R. Wilfred, David W. Fardo, Peter T. Nelson, Steven Estus

Research output: Contribution to journalArticlepeer-review

172 Scopus citations

Abstract

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 genesCD11bandAIF-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 where in SNP-modulated RNA splicing modulates CD33 function and, there by, AD risk.

Original languageEnglish
Pages (from-to)13320-13325
Number of pages6
JournalJournal of Neuroscience
Volume33
Issue number33
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Neuroscience (all)

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