Retinal pathological features and proteome signatures of Alzheimer’s disease.

Return to Grants

Publication Year:
2023
Authors:
Yosef Koronyo, Altan Rentsendorj, Nazanin Mirzaei, Giovanna C Regis, Julia Sheyn, Haoshen Shi, Ernesto Barron, Galen Cook-Wiens, Anthony R Rodriguez, Rodrigo Medeiros, Joao A Paulo, Veer B Gupta, Andrei A Kramerov, Alexander V Ljubimov, Jennifer E Van Eyk, Stuart L Graham, Vivek K Gupta, John M Ringman, David R Hinton, Carol A Miller, Keith L Black, Antonino Cattaneo, Giovanni Meli, Mehdi Mirzaei, Dieu-Trang Fuchs, Maya Koronyo-Hamaoui
PubMed ID:
36773106
Funding Grants:
Public Summary:
Researchers have discovered that signs of Alzheimer’s disease (AD) can also appear in the retina, the light-sensitive layer at the back of the eye. Because the retina is easy to look at, studying it could help doctors detect Alzheimer’s earlier and track its progression in a noninvasive way. In this study, scientists examined the eyes and brains of 86 people who had normal memory, mild cognitive impairment (MCI), or Alzheimer’s disease. They found higher levels of amyloid-beta proteins—the same harmful proteins that build up in the brain—in the retinas of people with MCI and Alzheimer’s. These proteins were especially concentrated in certain layers and outer areas of the retina. They also found more inflammation and tissue damage in the retinas of affected individuals, particularly in women. However, the immune cells in the retina were less able to clear out the amyloid buildup. Importantly, the amount of retinal damage closely matched the severity of Alzheimer’s-related changes in the brain and the patients’ memory test scores.
Scientific Abstract:
Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid beta-protein (Abeta(42)) forms and novel intraneuronal Abeta oligomers (AbetaOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Abeta uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Abeta(42), S100 calcium-binding protein B(+) macrogliosis, and atrophy correlated with severity of brain Abeta pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Abeta(42), far-peripheral AbetaOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.