{"doi":"10.1101/2025.05.06.652574","title":"Loss of endogenous tau suppresses APOE4-induced patterned behavioral decline and axon dysmorphia in a <i>C. elegans</i> model of Alzheimer’s disease","abstract":"Abstract Alzheimer’s disease (AD) causes a characteristic spatiotemporal pattern of neurodegeneration. The factors that account for this pattern of degeneration are unclear. Previously, we generated a model of AD using the nematode Caenorhabditis elegans with the AD risk variant of apolipoprotein E, APOE4 . We showed that HSN class neurons degenerate in early adult animals. Here, we perform behavioral analyses to deduce the effect of APOE4 on the function of distinct neuronal circuits. We found evidence that APOE4 induces dysfunction of other neurons; this spatiotemporal pattern roughly correlates with endogenous levels of PTL-1, the C. elegans homolog of human MAPT also known as tau. Moreover, deletion of ptl-1 suppressed defects in multiple behaviors, suggesting broad protective effects across the nervous system including the HSN neurons. Lastly, we show that PTL-1 in the touch receptor neurons, where PTL-1 is most abundant, contributes non-cell autonomously for age-related axon dysmorphia and dysfunction of the HSN neurons. Our results suggest that C. elegans may provide a useful in vivo system to study how endogenous tau acts downstream of APOE4 to cause progressive, patterned neurodegeneration.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":565713,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9504,"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":1469672,"name":"Chelsea J. Webber","orcid":null,"position":1,"is_corresponding":false},{"id":243372,"name":"Zheng Wu","orcid":"0000-0002-3816-8891","position":2,"is_corresponding":false},{"id":1250807,"name":"Blythe Bolton","orcid":null,"position":3,"is_corresponding":false},{"id":554327,"name":"Elif Sarinay Cenik","orcid":"0000-0001-8514-5505","position":4,"is_corresponding":false},{"id":385480,"name":"Jonathan T. Pierce","orcid":"0000-0002-9619-4713","position":5,"is_corresponding":false},{"id":1469671,"name":"Eric A. Cardona","orcid":null,"position":0,"is_corresponding":true}],"reference_count":127,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:32.546082Z","pmid":"40463229","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":[]}