{"doi":"10.1016/j.ebiom.2025.105924","title":"Therapeutic assessment of a novel mitochondrial complex I inhibitor in in vitro and in vivo models of Alzheimer's disease","abstract":"Background Despite recent approval of monoclonal antibodies that reduce amyloid (Aβ) accumulation, the development of disease-modifying strategies targeting the underlying mechanisms of Alzheimer's disease (AD) is urgently needed. Methods We demonstrate that mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signalling, benefiting AD mouse models with Aβ and p-Tau pathologies. Rational design and structure‒activity relationship studies yielded mtCI inhibitors profiled in a drug discovery funnel designed to address safety, selectivity, and efficacy. Findings The lead compound C458 is highly protective against Aβ toxicity, has favourable pharmacokinetics, and minimal off-target effects. C458 exhibited excellent brain penetrance, activating neuroprotective pathways with a single dose. Preclinical studies in APP/PS1 mice were conducted using functional tests, metabolic assessment, in vivo 31 P-NMR spectroscopy, blood cytokine panels, ex vivo electrophysiology, and Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis, antioxidant signalling, and cellular energetics. Efficacy against Aβ and p-Tau was confirmed in human organoids. Interpretation These studies provide further evidence that the restoration of mitochondrial function in response to mild energetic stress represents a promising disease-modifying strategy for AD. Funding This research was supported by grants from NIH AG 5549-06, NS1 07265, AG 062135, UG3/UH3 NS 113776, and ADDF 291204 (all to ET); U19 AG069701 (to TK); the Alzheimer's Association Research Fellowship grant 23AARF-1027342 (to TKON).","journal":"EBioMedicine","year":2025,"id":520125,"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":0.9635,"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":1050886,"name":"Thi Kim Oanh Nguyen","orcid":"0000-0002-6068-6222","position":1,"is_corresponding":false},{"id":482340,"name":"Andrea Stojakovic","orcid":"0000-0003-0046-7033","position":2,"is_corresponding":false},{"id":482342,"name":"Mark Ostroot","orcid":"0009-0009-1253-2120","position":3,"is_corresponding":false},{"id":1389702,"name":"J. Trey Deason","orcid":null,"position":4,"is_corresponding":false},{"id":307619,"name":"Su-Youne Chang","orcid":"0000-0001-8373-8921","position":5,"is_corresponding":false},{"id":1389131,"name":"Liang Zhang","orcid":"0000-0002-9463-3241","position":6,"is_corresponding":false},{"id":463938,"name":"Slobodan Macura","orcid":"0000-0002-6054-5163","position":7,"is_corresponding":false},{"id":1240657,"name":"Toshihiko Nambara","orcid":"0009-0001-3107-0680","position":8,"is_corresponding":false},{"id":234081,"name":"Wenyan Lü","orcid":null,"position":9,"is_corresponding":false},{"id":230892,"name":"Takahisa Kanekiyo","orcid":"0000-0001-6751-9374","position":10,"is_corresponding":false},{"id":107434,"name":"Eugenia Trushina","orcid":"0000-0002-6291-2860","position":11,"is_corresponding":false},{"id":570838,"name":"Sergey Trushin","orcid":"0000-0003-0470-6345","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:49:23.618703Z","pmid":"40957222","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":[]}