Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
Decoding amyloid beta clearance systems at inner blood-retina barrier using three-dimensional ex vivo retinal imaging in Alzheimer's disease.
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Wijesinghe Printha, Hosseini Amir, Campbell Matthew, Tejpal Shivani, Haynes Justin, Xi Jeanne, Mackenzie Ian R, Hirsch-Reinshagen Veronica, Hsiung Ging-Yuek Robin, Spiller Benjamin W, Wadzinski Brian E, Pham Wellington, Matsubara Joanne A
Аннотация
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.
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.