ArticleJournal of Alzheimer's disease : JAD2022
An Alternatively Spliced TREM2 Isoform Lacking the Ligand Binding Domain is Expressed in Human Brain.
Article in Journal of Alzheimer's disease : JAD, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 24 citations in OpenAlex.
- Uncovering the biological mechanisms of TREM2 with molecular simulations: A comprehensive review and perspective.Progress in biophysics and molecular biology · 2026Review
- TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.Cell communication and signaling : CCS · 2026Review
- Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes.Molecular neurodegeneration · 2026Article
- HMC3 revealed: how much do these "Microglia" really tell us?Frontiers in immunology · 2026Review
- Genetics of PLCG2 expression and splicing relative to Alzheimer's disease risk.Molecular neurodegeneration advances · 2026Article
- Roles of TREM2 in Alzheimer's disease.Translational neurodegeneration · 2025Review
- Is TREM2 a Stretch: Implications of TREM2 Along Spinal Cord Circuits in Health, Aging, Injury, and Disease.Cells · 2025Review
- Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes.bioRxiv : the preprint server for biology · 2025Article
- Review
- Celebrating 40 years of the University of Kentucky Alzheimer's Disease Research Center.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq.Nature biotechnology · 2025Article
- Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing.Nature genetics · 2025Article
- A Computational Approach in the Systematic Search of the Interaction Partners of Alternatively Spliced TREM2 Isoforms.International journal of molecular sciences · 2024Article
- TREM2 variants that cause early dementia and increase Alzheimer's disease risk affect gene splicing.Brain : a journal of neurology · 2024Article
- TREM2 function in glioblastoma immune microenvironment: Can we distinguish reality from illusion?Neuro-oncology · 2024Article
- More than microglia: myeloid cells and biomarkers in neurodegeneration.Frontiers in neuroscience · 2024Review
- A novelFrontiers in cellular neuroscience · 2024Article
- Using deep long-read RNAseq in Alzheimer's disease brain to assess medical relevance of RNA isoform diversity.bioRxiv : the preprint server for biology · 2023Article
- Long-read RNA-seq atlas of novel microglia isoforms elucidates disease-associated genetic regulation of splicing.medRxiv : the preprint server for health sciences · 2023Article
- Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation.Acta neuropathologica · 2023Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
backgroundGenetic variants in TREM2 are strongly associated with Alzheimer's disease (AD) risk but alternative splicing in TREM2 transcripts has not been comprehensively described.
objectiveRecognizing that alternative splice variants can result in reduced gene expression and/or altered function, we sought to fully characterize splice variation in TREM2.
methodsHuman 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.
resultsIn 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.
conclusionSince 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.
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