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.