{"doi":"10.7554/elife.90690.1","title":"Alzheimer’s disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling","abstract":"Abstract Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75 and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.","journal":null,"year":2023,"id":413578,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1119880,"name":"Utpal Das","orcid":"0000-0002-1635-9849","position":1,"is_corresponding":false},{"id":1119881,"name":"Sam Lismont","orcid":"0000-0001-5825-9590","position":2,"is_corresponding":false},{"id":1119882,"name":"Thomas Enzlein","orcid":"0000-0003-1789-4090","position":3,"is_corresponding":false},{"id":367420,"name":"Masato Maesako","orcid":"0000-0002-1970-2462","position":4,"is_corresponding":false},{"id":1194626,"name":"CQ Houser Mei","orcid":null,"position":5,"is_corresponding":false},{"id":745910,"name":"María Luisa Franco","orcid":"0000-0001-5119-4464","position":6,"is_corresponding":false},{"id":1119884,"name":"Diana Gomes Moreira","orcid":"0000-0003-2937-1772","position":7,"is_corresponding":false},{"id":1195165,"name":"Karachentsev Dmitry","orcid":null,"position":8,"is_corresponding":false},{"id":1195166,"name":"Becker Ann","orcid":null,"position":9,"is_corresponding":false},{"id":663105,"name":"Carsten Hopf","orcid":"0000-0003-0802-6451","position":10,"is_corresponding":false},{"id":745915,"name":"Marçal Vilar","orcid":"0000-0002-9376-6544","position":11,"is_corresponding":false},{"id":367419,"name":"Oksana Berezovska","orcid":"0000-0003-4898-5788","position":12,"is_corresponding":false},{"id":226995,"name":"William C. Mobley","orcid":"0000-0002-6408-9548","position":13,"is_corresponding":false},{"id":349948,"name":"Lucía Chávez‐Gutiérrez","orcid":"0000-0002-8239-559X","position":14,"is_corresponding":false},{"id":1119879,"name":"Katarzyna Marta Zoltowska","orcid":"0000-0001-5853-3465","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T01:21:57.641539Z","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":[]}