Transport of β-amyloid from Brain to Eye Causes Retinal Degeneration in Alzheimer’s Disease

Abstract

Purpose : Alzheimer's disease (AD) patients exhibit visual defects, β-amyloid (Aβ) deposits, and vascular-related pathological changes in the retina. We conducted research on the eyes of AD patients and 5xFAD mice to investigate whether Aβ deposition in the retina is transported from the brain. Additionally, we explored the molecular mechanisms of the brain-eye glymphatic system in AD retinopathy.

Methods : We histologically examined the deposition locations of Aβ in the eyes of AD patients and 5×FAD mice. we then assessed the visual function of 5×FAD mice and retinal pathological changes. Using various techniques like scRNA-seq, immunofluorescence, and Western blot, we detected proteins associated with Aβ generation in the AD retina. Furthermore, we explored the transportation of exogenous Aβ along the brain-eye pathway to the retina through cerebrospinal fluid (CSF) tracing experiments, mouse MRI, and bioluminescence imaging, and examined visual impairment due to long-term accumulation. We also investigated the molecular mechanisms of how Aquaporin-4 (AQP4) regulates the ocular glymphatic pathway to facilitate Aβ clearance with AD mice, aged mice, AQP4 knockout mice.

Results : We discovered Aβ deposits along the ocular glymphatic system in AD patients and 5×FAD transgenic mouse model. Interestingly, the ocular Aβ deposition in 5×FAD mice was not caused by local overproduction within the eyes but by the drainage of amyloid protein from CSF along the optic nerve, leading to retinal degeneration. AQP4 facilitates the influx of Aβ in brain-eye transport, out-excretion of the retina, and efflux in the eye-brain transport. Disrupted polarity or absence of AQP4 results in a slow entry and exit of brain-derived Aβ in the ocular glymphatic system, ultimately accumulating Aβ and exacerbating retinal degeneration. Moreover, oral administration of Omega-3 for 3 weeks alleviated impairments of AQP4 polarity in the retina of mice that received intracisternal injection of Aβ, thereby mitigating ocular degeneration.

Conclusions : The Aβ deposition in the AD retina is transported via the brain-eye glymphatic pathway. Our research reveals a novel mechanism of retinal degeneration in AD and the importance of AQP4 in this brain-eye glymphatic pathway.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Aβ deposits in the retina, optic nerve vasculature, and periorbital lymphatics of AD patients

 

The Aβ deposition in the AD retina is transported via the brain-eye glymphatic pathway