Retinal dysfunction in Alzheimer's disease mouse models

项目摘要 阿尔茨海默氏病（AD）是最常见的痴呆，导致记忆的进行性损害， 思考并影响着全世界数百万老年人，无法治愈。眼睛作为中枢神经的一部分 系统，表现出AD的一系列缺陷，如视网膜变薄，神经节细胞损失，微血管缺陷和 米勒细胞功能障碍。眼睛为研究神经和血管缺陷提供了透明的窗口， 可以帮助AD生物标志物的开发。这项补助金补充将利用眼睛的这一独特位置 在研究AD的病理学方面具有开发用于评估AD的生物标志物的潜力。它建立 在当前R01EY027779的坚实基础上，包括眼部表型和功能评估， Kif4.1通道的Müller细胞，但扩展的工作从糖尿病视网膜病变到AD。 晚发性AD（LOAD）是AD最常见的形式，遗传学在AD发病机制中起关键作用， 以载脂蛋白E4（APOE4）为主导因子。模式生物开发和晚发型评价 阿尔茨海默病（MODEL-AD）是一个正在开发下一代小鼠模型的财团 与LOAD相关并表征这些模型中的各种表型。我们将利用这一独特的模式- AD资源，用于研究APOE4KI小鼠（LOAD-风险）与APOE3KI（LOAD-风险）的眼部表型 中性）。我们务实的研究设计将首先在一系列视觉功能测定中表征这些小鼠， 探索他们视网膜转录组的神经变性标志物，并与脑组织进行比较， 研究Müller细胞中的Kir4.1通道，其中APOE 4主要集中。在第二组研究中，我们 激发这些小鼠进行高脂饮食治疗，以研究高血糖环境中的视网膜功能， APOE4基因型的存在是否会导致糖尿病视网膜病变（DR）表型，最常见的 糖尿病并发症。上述研究设计是基于我们的初步数据，这些数据表明血管 在APOE 4动物模型中，高脂饮食可导致脑功能缺陷和血糖升高。确保 该项目的成功，我们已经聚集了一个专家团队在眼睛和AD研究。 本增刊中的研究将以多种方式推进AD研究领域：（i）视网膜病变的研究 血管系统可能有助于AD的早期诊断;（ii）转录组学将识别AD中改变的新靶点 视网膜，这将有助于了解疾病的发病机制和未来的药物开发;（iii）脑Kir4.1 在AD中，APOE通道下调;然而，APOE 4如何影响其功能尚不清楚。我们的研究将 指向这个方向的研究机制;（iv）DR是一种致盲性眼病，AD患者 我们的研究将揭示这两种病理之间的联系;（v）我们的研究将揭示这两种病理之间的联系。 研究将有助于MODEL AD的目标，即表征AD模型的表型，并建立一个 未来模型的视觉评估范例。

Project Summary Alzheimer’s disease (AD) is the most common dementia resulting in progressive impairment in memory and thinking and affecting millions of older adults worldwide, with no cure. The eye, as part of the central nervous system, exhibits a range of defects in AD, such as retinal thinning, ganglion cell loss, microvascular deficit and Müller cell dysfunction. The eye provides a transparent window for studying neural and vascular defects, thus can aid in biomarker development in AD. This grant supplement will capitalize on this unique position of the eye in studying pathological aspects of AD with the potential to develop biomarkers for assessment of AD. It builds on the solid foundation of the current R01EY027779, including ocular phenotyping and functional assessment of Kif4.1 channels in Müller cells, but extends the work from diabetic retinopathy into AD. Late-onset AD (LOAD) is the most common form of AD, and genetics plays a critical role in AD pathogenesis, with apolipoprotein e4 (APOE4) as a leading factor. Model Organism Development & Evaluation of Late-Onset Alzheimer’s disease (MODEL-AD) is a consortium that is developing the next generation of mouse models relevant to LOAD and characterizing various phenotypes in these models. We will leverage this unique MODEL- AD resource to study the ocular phenotype in APOE4KI mice (LOAD-risk) in comparison to APOE3KI (LOAD- neutral). Our pragmatic study design will first characterize these mice in a series of visual function assays, explore their retinal transcriptome for markers of neurodegeneration and compare with that of brain tissue, and study Kir4.1 channels in Müller cells, where APOE4 is mainly concentrated. In a second set of studies, we will challenge these mice to high-fat diet treatment to study retinal function in the hyperglycemic milieu and test whether the presence of APOE4 genotype precipitates a diabetic retinopathy (DR) phenotype, the most common complication of diabetes. The above study design is based on our preliminary data which demonstrate a vascular deficit in the brain and increased blood glucose in response to a high-fat diet in APOE4 animal models. To ensure the success of the project, we have gathered a team of experts in both eye and AD research. The research in this supplement will advance the AD research field in a variety of ways: (i) study of retinal vasculature may aid in the early diagnosis of AD; (ii) transcriptomics will identify novel targets altered in AD retinas, which will help in understanding the disease pathogenesis and future drug development; (iii) brain Kir4.1 channels are downregulated in AD; however, how APOE4 affects their function is not known. Our studies will point towards studying mechanisms in this direction; (iv) DR is a blinding eye condition, and AD patients demonstrate a correlation with DR. Our studies will shed light on the link between these two pathologies; (v) our studies will contribute to MODEL-AD’s goal of characterizing the phenotype of AD models and establish a paradigm for ocular assessments of future models.