{"doi":"10.1002/alz.14481","title":"Lactylation of tau in human Alzheimer's disease brains","abstract":"INTRODUCTION: Aggregation of hyperphosphorylated tau (tauopathy) is associated with cognitive impairment in patients with Alzheimer's disease (AD). In AD, a metabolic shift due to the Warburg effect results in increased lactate production. Lactate can induce a post-translational modification (PTM) on proteins that conjugates lactyl groups to lysine (K) residues, which is known as lactylation. METHODS: We analyzed lactylation of tau in control and AD brain tissue and conducted cell-based assays. In addition, we used in vitro assays to determine whether p300 catalyzed tau lactylation. RESULTS: Quantitative proteomics detected that tau lactylation was elevated in AD brains, with K residue at position 331 (K331) being a prominent site. Lactate induced tau lactylation, which increased tau phosphorylation and cleavage and reduced ubiquitination. Inhibition of lactate production lowered tau lactylation; p300 catalyzed tau lactylation. DISCUSSION: Our findings suggest that tau lactylation links metabolic dysregulation with tauopathy and could serve as a novel diagnostic and therapeutic target. HIGHLIGHTS: Elevated tau lactylation, particularly at K331, is evident in in human AD brain samples. Lactate induces tau lactylation, enhancing phosphorylation and cleavage while inhibiting ubiquitination. The acetyl-transferase p300 catalyzes tau lactylation, with K331 being the most prominent site.","journal":"Alzheimer s & Dementia","year":2024,"id":421747,"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":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"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":233863,"name":"Yan Liu","orcid":"0000-0002-3961-9172","position":1,"is_corresponding":false},{"id":1215271,"name":"Michaella J. Rekowski","orcid":null,"position":2,"is_corresponding":false},{"id":670377,"name":"Ning Wang","orcid":"0000-0003-4647-5880","position":3,"is_corresponding":false},{"id":305894,"name":"Xiaoyu Zhang","orcid":"0000-0002-2555-0311","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T01:57:41.370244Z","pmid":"39740133","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":[]}