Single-Cell Transcriptomic Analysis of Human Retina

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PROJECT SUMMARY Alzheimer's Disease (AD) is a progressive neurodegenerative disease that affects 5.2 million Americans and 35 million worldwide. Pathologically, AD is characterized by deposits of extra-cellular amyloid plaques and neurofibrillary tangles. The retina and the brain have been found to be associated with a range of neurological diseases including AD and respond similarly to neuropathological conditions. Mounting evidence has suggested that AD also results in visual deficits, and pathological changes in the retinas of AD patients that include extensive loss of optic nerve and retinal ganglion cells, thinning of the retinal nerve fiber layer, and vascular abnormalities. As a projection of the central nervous system, the retina shares many cell types found in the brain including neurons, astrocytes, microglia, microvasculature, and a blood-retina barrier. Amyloid precursor protein is synthesized in retinal ganglion cells and is transported by the axons of the optic nerve to the brain. Additional proteins of the amyloid cascade are expressed by retinal neurons and glia. Further, amyloid beta plaques have been described in all retinal layers in animal models of AD. Histologically in humans, there is evidence of retinal thinning in AD patients and amyloid plaques in postmortem retinas of patients with early stage AD. Despite increasing evidence of retina involvement in AD, the underlying molecular and cellular mechanisms for these changes in the retina are still poorly understood. Another important factor in AD is the role of neuroinflammation. Although neuroinflammatory responses are commonly described in the brain of AD patients and animal models, only few studies have described retinal glia alterations in AD. In this project, we will test the hypothesis that measureable anatomical and molecular deficits occur in the retinas of individuals diagnosed with AD, and the retinal gene expression changes correlate with gene expression changes in the brain of individuals diagnosed with AD. Collaborating with the Alabama Eye Bank, the leader in rapid eye tissue recovery, we will perform single-cell RNA sequencing coupled to Spatial Transriptomics of the human retina in postmortem donors with AD, with the goal of identifying cells that are contributing to the development of AD pathology in the retina. Results from this pilot study will allow us to have a better understanding on the molecular and cellular variations of retinal changes in AD.