{"doi":"10.3233/jad-215602","title":"An Alternatively Spliced TREM2 Isoform Lacking the Ligand Binding Domain is Expressed in Human Brain","abstract":"<jats:p>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.</jats:p>","journal":"Journal of Alzheimer's Disease","year":2022,"id":31773,"datarank":0.8388085438294082,"base_score":3.2188758248682006,"endowment":3.2188758248682006,"self_citation_contribution":0.48283137373023016,"citation_network_contribution":0.35597717009917795,"self_endowment_contribution":0.48283137373023016,"citer_contribution":0.35597717009917795,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":17,"citers_with_citation_signal":16,"citers_with_endowment":16,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":169219,"name":"Henry C. 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Shaw","orcid":"0000-0001-8862-3840","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":3.2188758248682006,"endowment":3.2188758248682006,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35527547","pmcid":"PMC9335121","openalex_id":"https://openalex.org/W4225318404","authors":[],"funders":[{"funder_name":"NIA NIH HHS","grant_id":"R21 AG068370","title":null},{"funder_name":"NIA NIH HHS","grant_id":"P30 AG072946","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"F99 NS120365","title":null},{"funder_name":"NIA NIH HHS","grant_id":"RF1 AG059717","title":null},{"funder_name":"National Institutes of Health","grant_id":"3P30AG072946-02S1","title":"Portable and modular UDS Data Collection software to increase collaboration and engagement of Alzheimer’s Disease Research Center research software engineers"},{"funder_name":"National Institutes of Health","grant_id":"1F99NS120365-01A1","title":"Translating Genetic Risk Factors to Therapies: From Big Data to Druggable Targets"},{"funder_name":"National Institutes of Health","grant_id":"1RF1AG059717-01","title":"Translating SHIP1 genetics to generate a novel Alzheimer's pharmacologic agent"},{"funder_name":"National Institutes of Health","grant_id":"1R21AG068370-01","title":"How does D2-CD33 reduce Alzheimer's disease risk?"}],"total_grants":8,"fwci":2.0308,"citation_percentile":0.87436577,"influential_citations":1,"citation_trend":[{"year":2022,"count":2},{"year":2023,"count":6},{"year":2024,"count":8},{"year":2025,"count":8}],"oa_status":"green","license":"CC BY NC ND","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9335121","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335121","host_type":"GREEN"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9335121","host_type":"repository"},{"url":"https://content.iospress.com/download?id=10.3233/JAD-215602","host_type":"publisher"},{"url":"https://doi.org/10.3233/jad-215602","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35527547","host_type":"repository"},{"url":"https://doi.org/10.1101/2021.11.23.469712","host_type":""},{"url":"https://www.biorxiv.org/content/biorxiv/early/2021/11/23/2021.11.23.469712.full.pdf","host_type":""}],"fields_of_study":["Neuroinflammation and Neurodegeneration Mechanisms","Neurological Disease Mechanisms and Treatments","Axon Guidance and Neuronal Signaling","Biology","Medicine","0301 basic medicine","0303 health sciences","03 medical and health sciences","Alternative Splicing","Alzheimer Disease","Brain","Exons","Humans","Ligands","Membrane Glycoproteins","Protein Isoforms","Receptors, Immunologic"],"mesh_terms":["Alzheimer Disease","Brain","Exons","Humans","Ligands","Membrane Glycoproteins","Receptors, Immunologic","Alternative Splicing","Protein Isoforms"],"keywords":["Gene isoform","TREM2","Alternative splicing","Ligand (biochemistry)","Computational biology","Cell biology","Biology","Domain (mathematical analysis)","Human brain","Neuroscience","Receptor","Chemistry","Genetics","Gene","colocalization","Alzheimer’s disease","Gene Expression","Membrane Glycoproteins","Alzheimer Disease","Brain","Humans","Protein Isoforms","Exons","Receptors, Immunologic","Ligands"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"gen"},{"name":"ensembl"},{"name":"refsnp"},{"name":"refseq"},{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-09T08:34:54.569762Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}