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

Benjamin C. Shaw, Henry C. Snider, Andrew K. Turner, Diana J. Zajac, James F. Simpson, Steven Estus

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish
Pages (from-to)1647-1657
Number of pages11
JournalJournal of Alzheimer's Disease
Volume87
Issue number4
DOIs
StatePublished - 2022

Bibliographical note

Funding Information:
This work was supported by F99NS120365 (BCS), RF1AG059717 (SE), and R21AG068370 (SE). We would like to thank the Sanders-Brown Center on Aging Biorepository for samples, supported by P30 AG072946.

Publisher Copyright:
© 2022 - IOS Press. All rights reserved.

Keywords

  • Alternative splicing
  • Alzheimer's disease
  • colocalization
  • gene expression

ASJC Scopus subject areas

  • Neuroscience (all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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