An Alternatively Spliced TREM2 Isoform Lacking the Ligand Binding Domain is Expressed in Human Brain

J Alzheimers Dis. 2022;87(4):1647-1657. doi: 10.3233/JAD-215602.

Abstract

Background: Genetic variants in TREM2 are strongly associated with Alzheimer's disease (AD) risk but alternative splicing in TREM2 transcripts has not been comprehensively described.

Objective: Recognizing that alternative splice variants can result in reduced gene expression and/or altered function, we sought to fully characterize splice variation in TREM2.

Methods: Human anterior cingulate autopsy tissue from 61 donors was used for end-point and quantitative PCR and western blotting to identify and quantify novel TREM2 isoforms.

Results: In addition to previously described transcripts lacking exon 3 or exon 4, or retaining part of intron 3, we identified novel isoforms lacking exon 2, along with isoforms lacking multiple exons. Isoforms lacking exon 2 were predominant at approximately 10% of TREM2 mRNA in the brain. Expression of TREM2 and frequency of exon 2 skipping did not differ between AD samples and non-AD controls (p = 0.1268 and p = 0.4909, respectively). Further, these novel splice isoforms were also observed across multiple tissues with similar frequency (range 5.3 -13.0%). We found that the exon 2 skipped isoform D2-TREM2 is translated to protein and localizes similarly to full-length TREM2 protein, that both proteins are primarily retained in the Golgi complex, and that D2-TREM2 is expressed in AD and non-AD brain.

Conclusion: Since the TREM2 ligand binding domain is encoded by exon 2, and skipping this exon retains reading frame while conserving localization, we hypothesize that D2-TREM2 acts as an inhibitor of TREM2 and targeting TREM2 splicing may be a novel therapeutic pathway for AD.

Keywords: Alternative splicing; Alzheimer’s disease; colocalization; gene expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing*
  • Alzheimer Disease
  • Brain* / metabolism
  • Exons / genetics
  • Humans
  • Ligands
  • Membrane Glycoproteins* / genetics
  • Membrane Glycoproteins* / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Receptors, Immunologic* / genetics
  • Receptors, Immunologic* / metabolism

Substances

  • Ligands
  • Membrane Glycoproteins
  • Protein Isoforms
  • Receptors, Immunologic
  • TREM2 protein, human