Retinal dysfunction in Alzheimer's disease mouse models

项目摘要 阿尔茨海默病(AD)是最常见的痴呆症，会导致记忆和 思考并影响全球数百万老年人，但没有治愈方法。眼睛，作为中枢神经的一部分 在AD中表现出一系列的缺陷，如视网膜变薄，神经节细胞丢失，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一个透明的窗口，因此 可以帮助AD的生物标记物的发展。这项补助将利用眼睛的这一独特位置。 在研究AD的病理方面，有可能开发用于评估AD的生物标记物。它构建了 关于目前R01EY027779的坚实基础，包括眼部表型和功能评估 Kif4.1在Müler细胞中进行通路，但将工作从糖尿病视网膜病变延伸到AD。 晚发性AD(LOAD)是AD最常见的表现形式，遗传学在AD的发病机制中起着关键作用。 载脂蛋白e4(Apoe4)为主导因子。模式生物的发展及对迟发性的评价 阿尔茨海默病(模型-AD)是一个正在开发下一代小鼠模型的联盟 与这些模型中的各种表型的负载和特征相关。我们将利用这一独特的模式- AD资料：比较APOE4KI(LOAD-RISK)和APOE3KI(LOAD-RISK)小鼠的眼部表型 中性)。我们的务实研究设计将首先通过一系列视觉功能测试来表征这些小鼠， 探索它们的视网膜转录组以寻找神经变性的标志，并与脑组织的转录组进行比较 研究Müler细胞中的Kir4.1通道，其中APOE4主要集中在Müler细胞。在第二组研究中，我们将 对这些小鼠进行高脂饮食治疗，以研究高血糖环境下的视网膜功能，并进行测试 APOE4基因的存在是否会导致最常见的糖尿病视网膜病变(DR)表型 糖尿病并发症。上述研究设计是基于我们的初步数据，这些数据显示了一种血管 在APOE4动物模型中，高脂饮食导致脑部缺陷和血糖升高。为了确保 为了项目的成功，我们聚集了一支眼睛和AD研究方面的专家团队。 本增刊的研究将以多种方式推动AD研究领域的发展：(1)视网膜研究 血管系统可能有助于AD的早期诊断；(Ii)转录学将识别AD中改变的新靶点 视网膜，这将有助于了解该病的发病机制和未来的药物开发；(Iii)脑Kir4.1 通道在AD中下调；然而，APOE4如何影响其功能尚不清楚。我们的研究将 研究这一方向的机制；(Iv)DR是一种失明的眼睛状况，AD患者 我们的研究将阐明这两种病理之间的联系；(V)我们的 研究将有助于模型AD的目标，即表征AD模型的表型，并建立 目视评估未来模式的范例。

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.