ArticleJournal of leukocyte biology2021
Novel TREM2 splicing isoform that lacks the V-set immunoglobulin domain is abundant in the human brain.
Article in Journal of leukocyte biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 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
- Roles of TREM2 in Alzheimer's disease.Translational neurodegeneration · 2025Review
- TREM2 and sTREM2 in Alzheimer's disease: from mechanisms to therapies.Molecular neurodegeneration · 2025Review
- 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
- Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer's disease.Molecular neurodegeneration · 2024Article
- A novelFrontiers in cellular neuroscience · 2024Article
- Decoding sTREM2: its impact on Alzheimer's disease - a comprehensive review of mechanisms and implications.Frontiers in aging neuroscience · 2024Review
- 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
- Association between Cerebrospinal Fluid SolubleJournal of clinical medicine · 2023Article
- Genetic models of cleavage-reduced and soluble TREM2 reveal distinct effects on myelination and microglia function in the cuprizone model.Journal of neuroinflammation · 2023Article
- Profile ofInternational journal of molecular sciences · 2022Article
- Soluble TREM2: Innocent bystander or active player in neurological diseases?Neurobiology of disease · 2022Review
- An Alternatively Spliced TREM2 Isoform Lacking the Ligand Binding Domain is Expressed in Human Brain.Journal of Alzheimer's disease : JAD · 2022Article
- Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 ofInternational journal of molecular sciences · 2021Article
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7 authors at 2 institutions in 1 country.
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Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is an immunoglobulin-like receptor expressed by certain myeloid cells, such as macrophages, dendritic cells, osteoclasts, and microglia. In the brain, TREM2 plays an important role in the immune function of microglia, and its dysfunction is linked to various neurodegenerative conditions in humans. Ablation of TREM2 or its adaptor protein TYROBP causes polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (also known as Nasu-Hakola disorder) with early onset of dementia, whereas some missense variants in TREM2 are associated with an increased risk of late-onset Alzheimer's disease. The human TREM2 gene is subject to alternative splicing, and its major, full-length canonic transcript encompasses 5 exons. Herein, we report a novel alternatively spliced TREM2 isoform without exon 2 (Δe2), which constitutes a sizable fraction of TREM2 transcripts and has highly variable inter-individual expression in the human brain (average frequency 10%; range 3.7-35%). The protein encoded by Δe2 lacks a V-set immunoglobulin domain from its extracellular part but retains its transmembrane and cytoplasmic domains. We demonstrated Δe2 protein expression in TREM2-positive THP-1 cells, in which the expression of full-length transcript was precluded by CRISPR/Cas9 disruption of the exon 2 coding frame. Similar to the full-length TREM2, Δe2 is sorted to the plasma membrane and is subject to receptor shedding. In "add-back" experiments, Δe2 TREM2 had diminished capacity to restore phagocytosis of amyloid beta peptide and promote IFN-I response as compared to full-length TREM2. Our findings suggest that changes in the balance of two mutually exclusive TREM2 isoforms may modify the dosage of full-length transcript potentially weakening some TREM2 receptor functions in the human brain.
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