Retinal dysfunction in Alzheimer's disease mouse models

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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.