{"doi":"10.1002/alz.70592","title":"Decoding amyloid beta clearance systems at inner blood–retina barrier using three‐dimensional ex vivo retinal imaging in Alzheimer's disease","abstract":"INTRODUCTION: Impaired amyloid beta (Aβ) clearance contributes to sporadic Alzheimer's disease (AD). This study investigated retinal Aβ clearance involving neuronal, glial, and vascular interactions at the inner blood-retina barrier (iBRB), a functional analog of the blood-brain barrier (BBB). METHODS: Retinal wholemounts from AD donors and controls were analyzed alongside transgenic amyloid precursor protein/presenilin 1 (APP-PS1) and non-carrier control mouse retinal cross-sections using three- and two-dimensional ex vivo imaging. RESULTS: AD neuroretinas displayed increased larger Aβ42 deposits, microglial elongation, and substantial reductions in macroglial support and water channel expression. The uptake of soluble Aβ oligomers (SAβOs) by peripheral macrophage-like, Aβ-binding myeloid lineage cells was also diminished. In APP-PS1 mice, elevated glia levels, alongside increased APP/Aβ expression, suggest gliosis and failures in clearance processes with disease progression. DISCUSSION: Ex vivo three-dimensional retinal imaging at the iBRB provides novel insights into Aβ clearance in AD, which is difficult to replicate in ex vivo brain studies at the BBB. HIGHLIGHTS: Impaired clearance mechanisms play a key role in sporadic AD. The iBRB serves as a functional analog to the BBB. At the iBRB, the glymphatic system and microglial phagocytosis help mitigate Aβ burden. Peripheral macrophage-like myeloid lineage cells may aid SAβO clearance. The imaging plane (surface vs cross-section) may affect AD pathogenesis findings.","journal":"Alzheimer s & Dementia","year":2025,"id":515256,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.896,"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":807316,"name":"Amir Hosseini","orcid":null,"position":1,"is_corresponding":false},{"id":297228,"name":"Matthew Campbell","orcid":"0000-0003-3325-240X","position":2,"is_corresponding":false},{"id":1380082,"name":"Shivani Tejpal","orcid":null,"position":3,"is_corresponding":false},{"id":776521,"name":"Justin R. Haynes","orcid":null,"position":4,"is_corresponding":false},{"id":1067024,"name":"Jeanne Xi","orcid":null,"position":5,"is_corresponding":false},{"id":58515,"name":"Ian R. Mackenzie","orcid":"0000-0003-3875-2972","position":6,"is_corresponding":false},{"id":856536,"name":"Veronica Hirsch‐Reinshagen","orcid":"0000-0003-0530-871X","position":7,"is_corresponding":false},{"id":253920,"name":"Ging‐Yuek Robin Hsiung","orcid":"0000-0002-8017-0856","position":8,"is_corresponding":false},{"id":484525,"name":"Benjamin W. Spiller","orcid":"0000-0001-5397-1028","position":9,"is_corresponding":false},{"id":866117,"name":"Brian E. Wadzinski","orcid":"0000-0002-2980-3697","position":10,"is_corresponding":false},{"id":747254,"name":"Wellington Pham","orcid":"0000-0002-8408-7611","position":11,"is_corresponding":false},{"id":747253,"name":"Joanne A. Matsubara","orcid":"0000-0002-6236-9191","position":12,"is_corresponding":false},{"id":530674,"name":"Printha Wijesinghe","orcid":"0000-0002-6548-4689","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:48:39.436300Z","pmid":"41047467","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":[]}