{"doi":"10.1046/j.1471-4159.2002.01138.x","title":"Failure of the interaction between presenilin 1 and the substrate of γ‐secretase to produce Aβ in insect cells","abstract":"<jats:title>Abstract</jats:title><jats:p>Aggregates of β‐amyloid peptide (Aβ) are the major component of the amyloid core of the senile plaques observed in Alzheimer's disease (AD). Aβ results from the amyloidogenic processing of its precursor, the amyloid precursor protein (APP), by β‐ and γ‐secretase activities. If β‐secretase has recently been identified and termed BACE, the identity of γ‐secretase is still obscure. Studies with knock‐out mice showed that presenilin 1 (PS1), of which mutations are known to be the first cause of inherited AD, is mandatory for the γ‐secretase activity. However, the proteolytic activity of PS1 remains a matter of debate. Here we used transfected Sf9 insect cells, a cellular model lacking endogenous β‐ and/or γ‐secretase activities, to characterize the role of BACE and PS1 in the amyloidogenic processing of human APP. We show that, in Sf9 cells, BACE performs the expected β‐secretase cleavage of APP, generating C99. We also show that C99, which is a substrate of γ‐secretase, tightly binds to the human PS1. Despite this interaction, Sf9 cells still do not produce Aβ. This strongly argues against a direct proteolytic activity of PS1 in APP processing, and points toward an implication of PS1 in trafficking/presenting its substrate to the γ‐secretase.</jats:p>","journal":"Journal of Neurochemistry","year":2002,"id":615089,"datarank":0.3453877639491069,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"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":364295,"name":"Pascal Kienlen‐Campard","orcid":"0000-0003-1086-2942","position":1,"is_corresponding":false},{"id":1532567,"name":"Jean‐Noël Octave","orcid":null,"position":2,"is_corresponding":false},{"id":1585189,"name":"Didier Pitsi","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Failure of the interaction between presenilin 1 and the substrate of γ‐secretase to produce Aβ in insect cells","abstract":"<jats:title>Abstract</jats:title><jats:p>Aggregates of β‐amyloid peptide (Aβ) are the major component of the amyloid core of the senile plaques observed in Alzheimer's disease (AD). Aβ results from the amyloidogenic processing of its precursor, the amyloid precursor protein (APP), by β‐ and γ‐secretase activities. If β‐secretase has recently been identified and termed BACE, the identity of γ‐secretase is still obscure. Studies with knock‐out mice showed that presenilin 1 (PS1), of which mutations are known to be the first cause of inherited AD, is mandatory for the γ‐secretase activity. However, the proteolytic activity of PS1 remains a matter of debate. Here we used transfected Sf9 insect cells, a cellular model lacking endogenous β‐ and/or γ‐secretase activities, to characterize the role of BACE and PS1 in the amyloidogenic processing of human APP. We show that, in Sf9 cells, BACE performs the expected β‐secretase cleavage of APP, generating C99. We also show that C99, which is a substrate of γ‐secretase, tightly binds to the human PS1. Despite this interaction, Sf9 cells still do not produce Aβ. This strongly argues against a direct proteolytic activity of PS1 in APP processing, and points toward an implication of PS1 in trafficking/presenting its substrate to the γ‐secretase.</jats:p>","is_dataset_classified":null,"base_score":2.302585092994046,"endowment":2.302585092994046,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"12423249","pmcid":null,"openalex_id":"https://openalex.org/W1621864303","authors":[],"funders":[],"total_grants":0,"fwci":0.782,"citation_percentile":0.69445826,"influential_citations":0,"citation_trend":[{"year":2018,"count":1}],"oa_status":"closed","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1046%2Fj.1471-4159.2002.01138.x","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.2002.01138.x","host_type":"publisher"},{"url":"https://doi.org/10.1046/j.1471-4159.2002.01138.x","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/12423249","host_type":"repository"},{"url":"http://hdl.handle.net/2078.1/9294","host_type":"repository"}],"fields_of_study":["Alzheimer's disease research and treatments","Cholinesterase and Neurodegenerative Diseases","Prion Diseases and Protein Misfolding"],"mesh_terms":["Alzheimer Disease","Animals","Cells, Cultured","Humans","Membrane Proteins","Neurons","Endopeptidases","Protein Binding","Protein Processing, Post-Translational","Transfection","Blotting, Western","Amyloid beta-Peptides","Aspartic Acid Endopeptidases","Amyloid beta-Protein Precursor","Rats, Wistar","Spodoptera","Protein Transport","Rats","Presenilin-1","Amyloid Precursor Protein Secretases"],"keywords":["Presenilin","Sf9","Alpha secretase","Amyloid precursor protein secretase","Senile plaques","Amyloid precursor protein","Chemistry","Protein precursor","Cell biology","Gamma secretase","Amyloid beta","Transfection","ADAM10","BACE1-AS","Endogeny","Cleavage (geology)","Biochemistry","Peptide","Alzheimer's disease","Biology","Enzyme","Transgene","Internal medicine","Medicine","Disease","Genetically modified mouse","Gene","Recombinant DNA","Spodoptera","Metalloproteinase"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T18:53:03.237545Z","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":[]}