The Alzheimer's disease-protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool

Shoib S Siddiqui, Stevan A Springer, Andrea Verhagen, Venkatasubramaniam Sundaramurthy, Frederico Alisson-Silva, Weiping Jiang, Pradipta Ghosh, Ajit Varki

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35 Citations (Scopus)
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The immunomodulatory receptor Siglec-3/CD33 influences risk for late-onset Alzheimer's disease (LOAD), an apparently human-specific post-reproductive disease. CD33 generates two splice variants: a full-length CD33M transcript produced primarily by the "LOAD-risk" allele and a shorter CD33m isoform lacking the sialic acid-binding domain produced primarily from the "LOAD-protective" allele. An SNP that modulates CD33 splicing to favor CD33m is associated with enhanced microglial activity. Individuals expressing more protective isoform accumulate less brain β-amyloid and have a lower LOAD risk. How the CD33m isoform increases β-amyloid clearance remains unknown. We report that the protection by the CD33m isoform may not be conferred by what it does but, rather, from what it cannot do. Analysis of blood neutrophils and monocytes and a microglial cell line revealed that unlike CD33M, the CD33m isoform does not localize to cell surfaces; instead, it accumulates in peroxisomes. Cell stimulation and activation did not mobilize CD33m to the surface. Thus, the CD33m isoform may neither interact directly with amyloid plaques nor engage in cell-surface signaling. Rather, production and localization of CD33m in peroxisomes is a way of diminishing the amount of CD33M and enhancing β-amyloid clearance. We confirmed intracellular localization by generating a CD33m-specific monoclonal antibody. Of note, CD33 is the only Siglec with a peroxisome-targeting sequence, and this motif emerged by convergent evolution in toothed whales, the only other mammals with a prolonged post-reproductive lifespan. The CD33 allele that protects post-reproductive individuals from LOAD may have evolved by adaptive loss-of-function, an example of the less-is-more hypothesis.

Original languageEnglish
Pages (from-to)15312-15320
Number of pages9
JournalThe Journal of biological chemistry
Issue number37
Publication statusPublished - 15 Sept 2017


  • Alleles
  • Alzheimer Disease/genetics
  • Amino Acid Motifs
  • Bacterial Proteins/metabolism
  • Cell Line
  • Cell Membrane/drug effects
  • Genetic Predisposition to Disease
  • Humans
  • Lipopolysaccharides/toxicity
  • Macrophage Activation/drug effects
  • Macrophages/drug effects
  • Microglia/cytology
  • N-Formylmethionine Leucyl-Phenylalanine/toxicity
  • Nerve Tissue Proteins/chemistry
  • Neuraminidase/metabolism
  • Neutrophil Activation/drug effects
  • Neutrophils/drug effects
  • Peroxisomes/drug effects
  • Phylogeny
  • Polymorphism, Single Nucleotide
  • Protein Interaction Domains and Motifs
  • Protein Isoforms/chemistry
  • Protein Sorting Signals
  • Protein Transport/drug effects
  • Sialic Acid Binding Ig-like Lectin 3/chemistry


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