Brain-to-eye β-amyloid deposits found in ocular glymphatic system in patients with Alzheimer disease

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Researchers in China reported finding β-amyloid (Aβ) deposits along the ocular glymphatic system in patients with Alzheimer disease (AD) and in a 5×FAD transgenic mouse model,¹ according to Quichen Cao. He is affiliated with the Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, and Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, both in Nanjing, China; the Department of Ophthalmology, Baylor College of Medicine, Houston; and the Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University.

Cao and colleagues explained that the changes associated with Alzheimer's disease extend beyond the brain to the liver, kidneys, and intestines,^2-4 in addition to the eye in which atypical pupillary responses, decreased contrast sensitivity and visual field defects occur frequently.⁵ These are accompanied by retinal damage, ie, degeneration of retinal ganglion cells, activation of glial cells, and narrowing of retinal blood vessels.^6-9 Other studies have documented Aβ plaques in the postmortem retina of patients with Alzheimer's disease and in Alzheimer's disease transgenic mouse models.^9-11

In one of the authors’ recent studies,¹² they found an ocular glymphatic clearance system for the retinal waste product to exit via the proximal optic nerve.

“Interestingly, both the brain and the ocular glymphatic systems are dependent on glial water channel aquaporin-4 (AQP4), which mediates rapid fluid transmembrane transport and water homeostasis in the central nervous system. Despite the discovery of the ocular glymphatic system, little is known about its role in Alzheimer's disease-related retinal degeneration,” they commented.

This study, the next in their research, investigated the retinopathy caused by Aβ in patients with Alzheimer's disease and 5×FAD mice, to elucidate the role of the AQP4-mediated ocular glymphatic system in the retinal degeneration induced by brain-derived Aβ.

Role and mechanism of AQP4

The authors reported that the AQP4 signals adjacent to the retina vessels and optic nerve vessels of 5×FAD mice are lower than those in age-matched wild-type groups, while non-vascular areas exhibited stronger AQP4 signals, suggesting disrupted AQP4 polarity in the retina and optic nerve. Reduced AQP4 polarity was also seen in the retinas and optic nerve tissue of patients with Alzheimer's disease.

“These changes in AQP4,” the investigators said, “may underlie the dysfunction of the ocular glymphatic system.”

Cao explained, “The absence of AQP4 or its disrupted polarity delays the influx rate of Aβ in the brain–eye pathway, hinders its long-term clearance from the retina, and impedes the drainage through the perivenous space-optic nerve meningeal lymphatics pathway. The obstruction of the clearance pathway in the ocular glymphatic system is a primary factor exacerbating retinal degeneration. This is a crucial factor contributing to the accumulation and pathology of retinal Aβ in AD patients and mice.”

The investigators concluded, “These results revealed brain-to-eye Aβ transport as a major contributor to Alzheimer's disease retinopathy, highlighting a new therapeutic avenue in ocular and neurodegenerative disease.”

References:

1. Cao Q, Yang S, Want X, et al. Transport of β-amyloid from brain to eye causes retinal degeneration in Alzheimer's disease. J Exp Med. 2024;221:e20240386; doi: 10.1084/jem.20240386. Epub 2024 Sep 24.

2. Arnold SE, Lee EB, Moberg PJ, et al. Olfactory epithelium amyloid-beta and paired helical filament-tau pathology in Alzheimer disease. Ann Neurol.2024;67:462-469; https://doi.org/10.1002/ana.21910

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5. Berisha F, Feke GT, Trempe CL, et al. Retinal abnormalities in early Alzheimer’s disease. Invest Ophthalmol Vis Sci. 2007;48:2285-2289; https://doi.org/10.1167/iovs.06-1029

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7. Frost S, Kanagasingam Y, Sohrabi H, et al. Retinal vascular biomarkers for early detection and monitoring of Alzheimer’s disease. Transl Psychiatry. 2013;:3:e233; https://doi.org/10.1038/tp.2012.150

8. Hart NJ, Koronyo Y, Black KL, Koronyo-Hamaoui M. Ocular indicators of Alzheimer’s: Exploring disease in the retina. Acta Neuropathol. 2016;132:767-787; https://doi.org/10.1007/s00401-016-1613-6

9. Koronyo Y, Biggs D, Barron E, et al. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease. JCI Insight. 2017;2:e93621; https://doi.org/10.1172/jci.insight.93621

10. Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, et al. Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage. 2011;54:S204-S217.

11. Shi H, Koronyo Y, Rentsendork A, et al. Identification of early pericyte loss and vascular amyloidosis in Alzheimer’s disease retina. Acta Neuropathol. 2020;139:813–836; https://doi.org/10.1007/s00401-020-02134-w

12. Wang X, Lou N, Eberhardt A, et al. An ocular glymphatic clearance system removes β-amyloid from the rodent eye. Sci Transl Med. 2020;12:eaaw3210; https://doi.org/10.1126/scitranslmed.aaw3210