Format

Send to

Choose Destination
Mol Neurodegener. 2019 May 8;14(1):18. doi: 10.1186/s13024-019-0319-3.

TREM2 brain transcript-specific studies in AD and TREM2 mutation carriers.

Del-Aguila JL1,2,3, Benitez BA1,2,3, Li Z1,2,3, Dube U1,2,3, Mihindukulasuriya KA1,2, Budde JP1,2,3, Farias FHG1,2,3, Fernández MV1,2,3, Ibanez L1,2,3, Jiang S1,3, Perrin RJ3,4,5, Cairns NJ3,4,5,6, Morris JC4,5, Harari O1,2,3,4, Cruchaga C7,8,9,10.

Author information

1
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
2
NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO, USA.
3
Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
4
Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
5
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
6
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
7
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
8
NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
9
Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
10
Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.

Abstract

BACKGROUND:

Low frequency coding variants in TREM2 are associated with Alzheimer disease (AD) risk and cerebrospinal fluid (CSF) TREM2 protein levels are different between AD cases and controls. Similarly, TREM2 risk variant carriers also exhibit differential CSF TREM2 levels. TREM2 has three different alternative transcripts, but most of the functional studies only model the longest transcript. No studies have analyzed TREM2 expression levels or alternative splicing in brains from AD and cognitively normal individuals. We wanted to determine whether there was differential expression of TREM2 in sporadic-AD cases versus AD-TREM2 carriers vs sex- and aged-matched normal controls; and if this differential expression was due to a particular TREM2 transcript.

METHODS:

We analyzed RNA-Seq data from parietal lobe brain tissue from AD cases with TREM2 variants (n = 33), AD cases (n = 195) and healthy controls (n = 118), from three independent datasets using Kallisto and the R package tximport to determine the read count for each transcript and quantified transcript abundance as transcripts per million.

RESULTS:

The three TREM2 transcripts were expressed in brain cortex in the three datasets. We demonstrate for the first time that the transcript that lacks the transmembrane domain and encodes a soluble form of TREM2 (sTREM2) has an expression level around 60% of the canonical transcript, suggesting that around 25% of the sTREM2 protein levels could be explained by this transcript. We did not observe a difference in the overall TREM2 expression level between cases and controls. However, the isoform which lacks the 5' exon, but includes the transmembrane domain, was significantly lower in TREM2- p.R62H carriers than in AD cases (p = 0.007).

CONCLUSION:

Using bulk RNA-Seq data from three different cohorts, we were able to quantify the expression level of the three TREM2 transcripts, demonstrating: (1) all three transcripts of them are highly expressed in the human cortex, (2) that up to 25% of the sTREM2 may be due to the expression of a specific isoform and not TREM2 cleavage; and (3) that TREM2 risk variants do not affect expression levels, suggesting that the effect of the TREM2 variants on CSF levels occurs at post-transcriptional level.

KEYWORDS:

Alzheimer’s disease; Brain transcripts; R47H; RNAseq; Risk variants; Soluble TREM2; TREM2

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center