{"doi":"10.1038/s42003-024-05767-9","title":"Rescue of ApoE4-related lysosomal autophagic failure in Alzheimer’s disease by targeted small molecules","abstract":"Homozygosity for the ε4 allele of APOE increases the odds of developing Alzheimer's by 12 to 15 times relative to the most common ε3;ε3 genotype, and its association with higher plaque loads comports with evidence that APOEε4 compromises autophagy. The ApoE4 protein specifically binds a cis element (\"CLEAR\") in the promoters of several autophagy genes to block their transcription. We used a multifaceted approach to identify a druggable site in ApoE4, and virtual screening of lead-like compounds identified small molecules that specifically bind to this site to impede ApoE4::DNA binding. We validated these molecules both in vitro and in vivo with models expressing ApoE4, including ApoE4 targeted-replacement mice. One compound was able to significantly restore transcription of several autophagy genes and protected against amyloid-like aggregation in a C. elegans AD model. Together, these findings provide proof-of-principle evidence for pharmacological remediation of lysosomal autophagy by ApoE4 via ApoE4-targeted lead molecules that represent a novel tack on neurodegenerative disorders.","journal":"Communications Biology","year":2024,"id":424447,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1221418,"name":"Narasimhappagari Jagadeesh","orcid":null,"position":1,"is_corresponding":false},{"id":1220909,"name":"Ling Liu","orcid":"0000-0001-6979-701X","position":2,"is_corresponding":false},{"id":995651,"name":"Akshatha Ganne","orcid":"0000-0003-4604-5194","position":3,"is_corresponding":false},{"id":473967,"name":"Srinivas Ayyadevara","orcid":"0000-0002-4572-6361","position":4,"is_corresponding":false},{"id":1081468,"name":"Ramani Atluri","orcid":null,"position":5,"is_corresponding":false},{"id":995970,"name":"Haarika Ayyadevara","orcid":null,"position":6,"is_corresponding":false},{"id":257437,"name":"Guy A. Caldwell","orcid":"0000-0002-8283-9090","position":7,"is_corresponding":false},{"id":458711,"name":"Robert J. Shmookler Reis","orcid":"0000-0002-4691-0734","position":8,"is_corresponding":false},{"id":479210,"name":"Steven W. Barger","orcid":"0000-0001-6049-6480","position":9,"is_corresponding":false},{"id":657398,"name":"W. Sue T. Griffin","orcid":"0000-0002-0405-7800","position":10,"is_corresponding":false},{"id":458708,"name":"Meenakshisundaram Balasubramaniam","orcid":"0000-0003-0273-8757","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T01:58:07.191194Z","pmid":"38191671","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":[]}