{"doi":"10.1101/2024.03.25.586662","title":"Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model","abstract":"Cellular senescence, characterized by expressing the cell cycle inhibitory proteins, is evident in driving age-related diseases. Senescent cells play a crucial role in the initiation and progression of tau-mediated pathology, suggesting that targeting cell senescence offers a therapeutic potential for treating tauopathy associated diseases. This study focuses on identifying non-invasive biomarkers and validating their responses to a well-characterized senolytic therapy combining dasatinib and quercetin (D+Q), in a widely used tauopathy mouse model, PS19. We employed human-translatable MRI measures, including water extraction with phase-contrast arterial spin tagging (WEPCAST) MRI, T2 relaxation under spin tagging (TRUST), longitudinally assessed brain physiology and high-resolution structural MRI evaluated the brain regional volumes in PS19 mice. Our data reveal increased BBB permeability, decreased oxygen extraction fraction, and brain atrophy in 9-month-old PS19 mice compared to their littermate controls. (D+Q) treatment effectively preserves BBB integrity, rescues cerebral oxygen hypometabolism, attenuates brain atrophy, and alleviates tau hyperphosphorylation in PS19 mice. Mechanistically, D+Q treatment induces a shift of microglia from a disease-associated to a homeostatic state, reducing a senescence-like microglial phenotype marked by increased p16/INK4a. D+Q-treated PS19 mice exhibit enhanced cue-associated cognitive performance in the tracing fear conditioning test compared to the vehicle-treated littermates, implying improved cognitive function by D+Q treatment. Our results pave the way for application of senolytic treatment as well as these noninvasive MRI biomarkers in clinical trials in tauopathy associated neurological disorders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":490495,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"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":57473,"name":"Zhiliang Wei","orcid":"0000-0002-8477-2440","position":1,"is_corresponding":false},{"id":1215230,"name":"Jonathan Scharff Nielsen","orcid":null,"position":2,"is_corresponding":false},{"id":57474,"name":"Aaron Kakazu","orcid":null,"position":3,"is_corresponding":false},{"id":57475,"name":"Yuxiao Ouyang","orcid":null,"position":4,"is_corresponding":false},{"id":57476,"name":"Ruoxuan Li","orcid":"0000-0001-6095-7945","position":5,"is_corresponding":false},{"id":729843,"name":"Tiffany Chu","orcid":"0000-0002-9455-0868","position":6,"is_corresponding":false},{"id":778177,"name":"Susanna Scafidi","orcid":"0000-0002-1229-8778","position":7,"is_corresponding":false},{"id":57482,"name":"Hanzhang Lu","orcid":"0000-0003-3871-1564","position":8,"is_corresponding":false},{"id":315583,"name":"Manisha Aggarwal","orcid":"0000-0001-5951-3271","position":9,"is_corresponding":false},{"id":57484,"name":"Wenzhen Duan","orcid":"0000-0001-5933-6308","position":10,"is_corresponding":false},{"id":57471,"name":"Minmin Yao","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:08:37.162700Z","pmid":"38585805","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":[]}