{"doi":"10.1101/2025.09.11.675671","title":"Pathogenic tau inhibits synaptic plasticity by blocking eIF4B-mediated local protein synthesis","abstract":"Activity-dependent modulation of synaptic strength is critical for encoding memories and it is inhibited in tauopathies including Alzheimer's disease (AD) and Frontotemporal lobar degeneration with tau inclusions (FTLD-tau). Pathogenic tau accumulates in neurons where it obstructs synaptic plasticity. How tau blocks synaptic plasticity leading to memory loss is unclear. Here, we show that FTLD-tau inhibits plasticity by blocking activity-dependent protein synthesis in dendrites. In the plasticity-associated translatome, we identified a subset of downregulated translated mRNAs in FTLD-tau neurons that encode postsynaptic plasticity regulators. Protein synthesis was blocked by FTLD-tau binding to eIF4B which caused eIF4B dissociation from the translation initiation complex and reduced dendritic eIF4B levels. Inhibiting the tau-eIF4B interaction or enhancing eIF4B levels in FTLD-tau neurons restored local protein synthesis and synaptic plasticity. Together, this suggests that pathogenic tau binding to eIF4B disables the local synthesis of plasticity-related proteins that drive synapse strengthening and memory formation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555761,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"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":1455074,"name":"Doyle Lokitiyakul","orcid":null,"position":1,"is_corresponding":false},{"id":618320,"name":"Ivy Tsz-Lo Wong","orcid":"0000-0002-9761-3422","position":2,"is_corresponding":false},{"id":1375622,"name":"Kevin Schneider","orcid":"0000-0003-4029-2995","position":3,"is_corresponding":false},{"id":1454600,"name":"Varun Sridhar","orcid":"0000-0003-1362-4130","position":4,"is_corresponding":false},{"id":652271,"name":"Durai Sellegounder","orcid":"0000-0002-0776-0307","position":5,"is_corresponding":false},{"id":1455075,"name":"Yani Y. Ngwala","orcid":null,"position":6,"is_corresponding":false},{"id":1167445,"name":"Lei Yao","orcid":"0000-0002-5780-5809","position":7,"is_corresponding":false},{"id":1167963,"name":"Jackson H. Chen","orcid":null,"position":8,"is_corresponding":false},{"id":1167962,"name":"Kristeen A. Pareja‐Navarro","orcid":null,"position":9,"is_corresponding":false},{"id":351745,"name":"Alissa L. Nana","orcid":"0000-0003-3474-8044","position":10,"is_corresponding":false},{"id":260466,"name":"Salvatore Spina","orcid":"0000-0003-3570-9143","position":11,"is_corresponding":false},{"id":32591,"name":"William W. Seeley","orcid":"0000-0003-1410-2027","position":12,"is_corresponding":false},{"id":109118,"name":"Lea T. Grinberg","orcid":"0000-0002-6809-0618","position":13,"is_corresponding":false},{"id":95315,"name":"Eric Verdin","orcid":"0000-0003-3703-3183","position":14,"is_corresponding":false},{"id":3338,"name":"David Furman","orcid":"0000-0002-3654-9519","position":15,"is_corresponding":false},{"id":301876,"name":"Celeste M. Karch","orcid":"0000-0002-6854-5547","position":16,"is_corresponding":false},{"id":250399,"name":"Li Gan","orcid":"0000-0003-4600-275X","position":17,"is_corresponding":false},{"id":250398,"name":"Tara E. Tracy","orcid":"0000-0003-3356-4091","position":18,"is_corresponding":false},{"id":776527,"name":"Grant Kauwe","orcid":null,"position":0,"is_corresponding":true}],"reference_count":101,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:03.976486Z","pmid":"41279029","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":[]}