Thursday, January 2, 2025
1/2/2025
PROJECT SUMMARY The retina, an outgrowth of the brain, is often referred to as the “window of the brain”. The retina and the brain are both associated with various neurological diseases, including Alzheimer's disease (AD) and age-related macular degeneration (AMD). AD and AMD share similar neuropathological conditions, with AD characterized by extra-cellular amyloid plaques and neurofibrillary tangles, and AMD diagnosed by the presence of drusen deposits. Mounting evidence suggests that AD also results in visual deficits and pathological changes in the retinas of AD patients, including the extensive loss of optic nerve and retinal ganglion cells, thinning of the retinal nerve fiber layer, and vascular abnormalities. Although the biochemical analysis of drusen deposits in AMD has shown remarkable similarities to the AD deposits, the underlying molecular mechanisms that lead to their similarity are still unknown. This study aims to identify shared cell types and common cellular pathways between AD and AMD through comparative single-cell data analysis. To achieve this goal, we propose two aims. Aim 1 will harmonize BRAIN Initiative generated single-cell RNA-seq (scRNA-seq) and single-nucleus RNA-seq (snRNA-seq) data with snRNA-seq data generated from AD brains to produce a fully harmonized, denoised, batch effect corrected, and annotated sc/snRNA-seq dataset that will be ready for differential gene expression and cell-cell communication analysis. Using the harmonized data obtained from Aim 1, Aim 2 will conduct cell-type-specific differential gene expression and cell-cell communication analysis between AD and normal brains. We will further conduct comparative analysis with cell-type-specific changes obtained from our parent R01 that focuses on AMD. By comparing the changes in AD brains and AMD eyes at the cell-type-specific level, we will identify shared cell types and common pathways between these two diseases. Findings from this application will address key knowledge gaps in the degeneration mechanisms of AD and AMD, elucidate the connections between these two diseases, and seed cell-specific functional studies, in vivo modeling, and precision therapeutic targeting of both AD and AMD.
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