Cell-associated Transcriptional Alterations in the Retinal of Alzheimer’s Disease

Abstract

Current approaches for studying pathologic changes in the retina associated with Alzheimer's Disease (AD) remain heterogeneous, limiting the use of retinal amyloid-beta as a viable biomarker for AD. Transcriptomic profiling of the retina has provided cell-specific insight into AD progression in the brain yet is lacking in the retina. In this study, we implemented a non-biased approach through next-generation sequencing to profile frozen archived retinal tissues from autopsy/pathologically confirmed AD and non-diagnosed cases (NonAD). A total of 37,211 nuclei were isolated from frozen retinal tissue punches originating from AD, and 31,326 were isolated from non-diagnosed cases. Gene expression patterns specific to the retinal region and major retinal cell types were represented in both tissue groups. AD-associated genes were differentially expressed in AD retinal glial cells, including microglia. A greater percentage of microglial nuclei from AD retinal nuclei expressed TYRO protein tyrosine kinase-binding protein (TYROBP) compared to nonAD retinal nuclei. However, compared to microglia from single retinal cell datasets from elderly non-diseased individuals, TYROBP expression is highly expressed in the single cell data set, indicating TYROBP transcripts reside within the cytoplasm. However, other AD-associated genes were differentially expressed in AD nuclei such as DOCK2, PICALM, and PLCG2 compared to non-diseased single-cell microglia, implicating a role of these genes in the AD retina. To summarize, we extracted a high number of nuclei from frozen retinal tissue that retain specific gene markers for cell classification and highlighted candidate AD-associated genes in retinal microglia that may be viable in future AD retinal studies.