{"doi":"10.1101/2022.06.02.494546","title":"Lysosomal dysfunction in Down Syndrome and Alzheimer mouse models is caused by selective v-ATPase inhibition by Tyr <sup>682</sup> phosphorylated APP βCTF","abstract":"Abstract Lysosome dysfunction arises early and propels Alzheimer’s Disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down Syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) to disrupt lysosomal v-ATPase and acidification. In human DS fibroblasts, the phosphorylated 682 YENPTY internalization motif of APP-βCTF binds selectively within a pocket of the v-ATPase V0a1 subunit cytoplasmic domain and competitively inhibits association of the V1 subcomplex of v-ATPase, thereby reducing its activity. Lowering APP-βCTF Tyr 682 phosphorylation restores v-ATPase and lysosome function in DS fibroblasts and in vivo in brains of DS model mice. Notably, lowering APP-βCTF Tyr 682 phosphorylation below normal constitutive levels boosts v-ATPase assembly and activity, suggesting that v-ATPase may also be modulated tonically by phospho-APP-βCTF. Elevated APP-βCTF Tyr 682 phosphorylation in two mouse AD models similarly disrupts v-ATPase function. These findings offer new insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":298273,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9626,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":266915,"name":"Ying Jiang","orcid":"0000-0003-2432-8011","position":1,"is_corresponding":false},{"id":266914,"name":"Philip Stavrides","orcid":"0000-0003-1225-3577","position":2,"is_corresponding":false},{"id":266917,"name":"Sandipkumar Darji","orcid":"0000-0003-4197-4971","position":3,"is_corresponding":false},{"id":291559,"name":"Hediye Erdjument‐Bromage","orcid":"0000-0003-0224-3594","position":4,"is_corresponding":false},{"id":291560,"name":"Thomas A. Neubert","orcid":"0000-0001-7049-2088","position":5,"is_corresponding":false},{"id":924011,"name":"Jun Yong Choi","orcid":"0000-0001-8218-6440","position":6,"is_corresponding":false},{"id":913473,"name":"Jerzy Węgiel","orcid":"0000-0002-3685-0694","position":7,"is_corresponding":false},{"id":266916,"name":"Ju‐Hyun Lee","orcid":"0000-0002-0280-8375","position":8,"is_corresponding":false},{"id":257655,"name":"Ralph A. Nixon","orcid":"0000-0001-5124-1021","position":9,"is_corresponding":false},{"id":806663,"name":"Eunju Im","orcid":"0000-0002-7839-8878","position":0,"is_corresponding":true}],"reference_count":95,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:36.269611Z","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":[]}