Single-Cell Transcriptomic Analysis of Human Retina

项目总结 阿尔茨海默病(AD)是一种进行性神经退行性疾病，影响520万美国人和 全球有3500万人。病理上，AD的特征是细胞外淀粉样斑块沉积和 神经原纤维缠结。视网膜和大脑已被发现与一系列神经学疾病有关 包括阿尔茨海默病在内的疾病，对神经病理情况的反应类似。越来越多的证据表明 提示AD还会导致视力障碍，并导致AD患者视网膜的病理变化 包括视神经和视网膜神经节细胞的广泛丢失，视网膜神经纤维层变薄，以及 血管异常。作为中枢神经系统的投影，视网膜具有许多已发现的细胞类型 在大脑中，包括神经元、星形胶质细胞、小胶质细胞、微血管系统和血-视网膜屏障。淀粉样蛋白 前体蛋白在视网膜神经节细胞中合成，并由视神经的轴突运输到 大脑。淀粉样蛋白级联的其他蛋白质由视网膜神经元和胶质细胞表达。此外， 在AD的动物模型中，所有视网膜层中都有淀粉样β斑块的描述。组织学上 人类，有证据表明AD患者的视网膜变薄，死后视网膜有淀粉样斑块。 早期阿尔茨海默病患者。尽管越来越多的证据表明视网膜参与了AD，但潜在的 视网膜这些变化的分子和细胞机制仍然知之甚少。另一个 阿尔茨海默病的重要因素是神经炎症的作用。尽管神经炎性反应通常是 在AD患者和动物模型的大脑中进行了描述，只有少数研究描述了视网膜胶质细胞 公元后的变化。在这个项目中，我们将检验可测量的解剖学和分子缺陷的假设 发生在诊断为AD的个体的视网膜，视网膜基因表达的变化与 阿尔茨海默病患者大脑中基因表达的变化。与阿拉巴马州之眼合作 Bank，快速眼组织恢复的领先者，我们将进行单细胞RNA测序耦合到Space 对患有AD的死后捐赠者进行视网膜移植，目的是识别 促进了视网膜中AD病理的发展。这项试点研究的结果将使我们能够 更好地了解阿尔茨海默病视网膜变化的分子和细胞变化。

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.