{"doi":"10.1186/s12967-025-07324-2","title":"Detection of extracellular amyloid beta aggregates by an Aducanumab-based synNotch receptor: an in vitro proof-of-concept study","abstract":"BACKGROUND: Synthetic Notch (synNotch) receptors are a powerful gene regulation platform that activate transcription in response to membrane-bound ligands and extracellular matrix components, with emerging applications in cancer, autoimmunity, and regenerative medicine. Whether synNotch can be adapted to detect and respond to extracellular neurotoxic protein aggregates-such as amyloid beta (Aβ), a hallmark of Alzheimer's disease (AD)-remains unknown. METHODS: To address this, we engineered an Aβ-responsive synNotch receptor (Adu-synNotch) by fusing the single-chain variable fragment (scFv) derived from Aducanumab (Aduhelm®), an FDA-approved anti-Aβ antibody, to the extracellular domain of synNotch. This construct was expressed in NIH 3T3 cells and paired with downstream reporters CLIP-tag, secreted Metridia luciferase (MetLuc), and synthetic expression cassettes encoding chimeric human-mouse versions of the therapeutic antibodies Lecanemab (Leqembi®) and Aducanumab. Cells were exposed to Aβ(1-42) aggregates, and synNotch activation was assessed via CLIP-tag imaging, MetLuc secretion assays, and immunocytochemistry for Lecanemab and Aducanumab. RESULTS: NIH 3T3 cells expressing Adu-synNotch responded to extracellular Aβ aggregates with robust induction of CLIP-tag and MetLuc reporters, along with secretion of chimeric Lecanemab and Aducanumab antibodies. Activation was dose-dependent and the secreted antibodies bound to Aβ aggregates, confirming that extracellular Aβ can serve as a functional synNotch ligand. CONCLUSIONS: These findings establish that synNotch receptors can be engineered to detect and respond to pathological extracellular protein aggregates such as Aβ. This expands the scope of synNotch-based systems and supports their potential for developing precision cell-based therapies for neurodegenerative diseases like AD.","journal":"Journal of Translational Medicine","year":2025,"id":548407,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1372685,"name":"Suckwon Lee","orcid":null,"position":1,"is_corresponding":false},{"id":987328,"name":"Cynthia J. Siebrand","orcid":"0000-0001-5422-1835","position":2,"is_corresponding":false},{"id":1442094,"name":"Zachary Mayeri","orcid":null,"position":3,"is_corresponding":false},{"id":321590,"name":"Julie K. Andersen","orcid":"0000-0003-1324-4875","position":4,"is_corresponding":false},{"id":321588,"name":"Chaska C. Walton","orcid":"0000-0001-8513-0207","position":5,"is_corresponding":false},{"id":1372684,"name":"Nicholas J. Bergo","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:53:58.530220Z","pmid":"41214730","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":[]}