{"doi":"10.64898/2025.12.30.697078","title":"Expression of the human immunomodulatory protein, human B7-1 (CD80), accelerates neuroinflammation, synaptic loss, microvascular instability and lethality in a murine model of Alzheimer’s Disease","abstract":"Abstract Immune-mediated inflammatory processes play a pivotal role in the pathogenesis of Alzheimer’s disease (AD). However, immune loci exhibit significant sequence diversity, with human proteins sharing only ∼45–70% identity with their murine orthologs. This divergence contributes to the inability of many established mouse models to accurately capture key neuroinflammatory mechanisms relevant to human AD. We recently identified that the human, but not murine, immunomodulatory protein B7-1 (CD80) activates the p75 neurotrophin receptor (p75), a function arising from evolutionary divergence in human B7-1. This discovery provides an opportunity to directly interrogate the role of this interaction in disease progression using a well-characterized murine model of mutant Aβ overexpression (CRND8). We generated a mouse line in which murine B7-1 was replaced with a chimeric human:murine B7-1 that retains normal interactions with CTLA-4 and CD28, while gaining the ability to bind p75, and evaluated its effects in CRND8 mice. Expression of human:murine B7-1 in vivo resulted in increased lethality, accelerated neuroinflammation of resident glia, more rapid synaptic and dendritic loss, and enhanced microvascular compromise in the subiculum compared to CRND8 mice expressing murine B7-1. Together, these findings identify the human B7-1:p75 interaction as a previously unrecognized contributor to AD pathogenesis and a potential therapeutic target in a brain region critical for learning and memory that is affected in early stages of disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":587618,"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":0.9547,"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":475729,"name":"Sarah C. Garrett-Thomson","orcid":"0000-0002-3073-1571","position":1,"is_corresponding":false},{"id":230346,"name":"Nicholas C. Morano","orcid":"0000-0002-8129-4033","position":2,"is_corresponding":false},{"id":1468462,"name":"Ruben Constanza","orcid":null,"position":3,"is_corresponding":false},{"id":367927,"name":"Pouneh Kermani","orcid":null,"position":4,"is_corresponding":false},{"id":1503274,"name":"Roshelle S. Smith","orcid":"0000-0001-5146-2297","position":5,"is_corresponding":false},{"id":230350,"name":"Steven C. Almo","orcid":"0000-0003-2591-5234","position":6,"is_corresponding":false},{"id":72619,"name":"Francis S. Lee","orcid":"0000-0002-7108-9650","position":7,"is_corresponding":false},{"id":517069,"name":"Barbara L. Hempstead","orcid":null,"position":8,"is_corresponding":false},{"id":1054979,"name":"Víctor Danelon","orcid":"0000-0003-1685-6164","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T02:59:39.958043Z","pmid":null,"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":[]}