{"doi":"10.1016/j.jbc.2022.101911","title":"The transmembrane domain of the amyloid precursor protein is required for antiamyloidogenic processing by α-secretase ADAM10","abstract":null,"journal":"Journal of Biological Chemistry","year":2022,"id":591083,"datarank":0.5411495313473516,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.1452909319050626,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.1452909319050626,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":10,"citers_with_citation_signal":9,"citers_with_endowment":9,"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":1512246,"name":"Thorsten Lang","orcid":null,"position":1,"is_corresponding":false},{"id":1512244,"name":"Lisa Hitschler","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The transmembrane domain of the amyloid precursor protein is required for antiamyloidogenic processing by α-secretase ADAM10","abstract":"Neurotoxic amyloid β-peptides are thought to be a causative agent of Alzheimer's disease in humans. The production of amyloid β-peptides from amyloid precursor protein (APP) could be diminished by enhancing α-processing; however, the physical interactions between APP and α-secretases are not well understood. In this study, we employed super-resolution light microscopy to examine in cell-free plasma membranes the abundance and association of APP and α-secretases ADAM10 (a disintegrin and metalloproteinase) and ADAM17. We found that both secretase molecules localize similarly closely to APP (within ≤50 nm). However, when cross-linking APP with antibodies directed against the GFP tag of APP, in confocal microscopy, we observed that only ADAM10 coaggregated with APP. Furthermore, we mapped the involved protein domain by using APP variants with an exchanged transmembrane segment or lacking cytoplasmic/extracellular domains. We identified that the transmembrane domain of APP is required for association with α-secretases and, as analyzed by Western blot, for α-processing. We propose that the transmembrane domain of APP interacts either directly or indirectly with ADAM10, but not with ADAM17, explaining the dominant role of ADAM10 in α-processing of APP. Further understanding of this interaction may facilitate the development of a therapeutic strategy based on promoting APP cleavage by α-secretases.","is_dataset_classified":null,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35398353","pmcid":"PMC9127328","openalex_id":"https://openalex.org/W4223480264","authors":[],"funders":[{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"unidentified","title":"unidentified"},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"","title":null}],"total_grants":2,"fwci":1.0994,"citation_percentile":0.76046171,"influential_citations":0,"citation_trend":[{"year":2022,"count":1},{"year":2023,"count":4},{"year":2024,"count":3},{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1016/j.jbc.2022.101911","host_type":"journal"},{"url":"https://doi.org/10.1016/j.jbc.2022.101911","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925822003519?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925822003519?httpAccept=text/plain","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35398353","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9127328","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9127328","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9127328?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1016/j.jbc.2022.101911","host_type":""}],"fields_of_study":["Alzheimer's disease research and treatments","Amyloidosis: Diagnosis, Treatment, Outcomes","14-3-3 protein interactions","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["ADAM10 Protein","ADAM17 Protein","Protein Domains","Alzheimer Disease","Humans","Membrane Proteins","Amyloid beta-Peptides","Amyloid beta-Protein Precursor","Amyloid Precursor Protein Secretases"],"keywords":["ADAM10","Amyloid precursor protein secretase","Amyloid precursor protein","Alpha secretase","Transmembrane domain","Transmembrane protein","Cell biology","Presenilin","P3 peptide","Chemistry","Extracellular","Disintegrin","Biochemistry","Biology","Metalloproteinase","Alzheimer's disease","Receptor","Matrix metalloproteinase","Medicine","Internal medicine","Disease","Amyloid beta","Secretases","Super-resolution Microscopy","Adam17","Amyloid beta-Peptides","Membrane Proteins","ADAM17 Protein","ADAM10 Protein","Amyloid beta-Protein Precursor","Protein Domains","Alzheimer Disease","Humans","Amyloid Precursor Protein Secretases","Research Article"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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