阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特点是Aβ斑块和神经原纤维缠结的积累，导致突触丢失和神经退化。视网膜是眼睛内中枢神经系统的延伸，与大脑在结构上有许多相似之处，并且先前的研究观察到视网膜中AD相关表型。由人类多能干细胞（hPSCs）分化的三维视网膜器官结构能有效模拟一些疾病状态的最早表现，然而早期AD相关表型尚未被研究。因此，本研究侧重于将hPSCs分化成视网膜器官结构，以分析早期AD相关改变。结果表明，无论是家族性AD还是未受影响的对照细胞系，都能得到较为稳定的视网膜器官结构分化，而家族性AD视网膜器官结构则显示出Aβ42:Aβ40比值和Tau蛋白磷酸化明显增加，具有AD病理学特征。此外，转录分析表明许多基因和细胞通路的差异表达，包括与突触功能障碍有关的通路。综上所述，本研究证明了视网膜器官结构作为鉴定与AD相关的早期视网膜改变的强大模型的能力。© 2023. Springer Nature Limited.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of Aβ plaques and neurofibrillary tangles, resulting in synaptic loss and neurodegeneration. The retina is an extension of the central nervous system within the eye, sharing many structural similarities with the brain, and previous studies have observed AD-related phenotypes within the retina. Three-dimensional retinal organoids differentiated from human pluripotent stem cells (hPSCs) can effectively model some of the earliest manifestations of disease states, yet early AD-associated phenotypes have not yet been examined. Thus, the current study focused upon the differentiation of hPSCs into retinal organoids for the analysis of early AD-associated alterations. Results demonstrated the robust differentiation of retinal organoids from both familial AD and unaffected control cell lines, with familial AD retinal organoids exhibiting a significant increase in the Aβ42:Aβ40 ratio as well as phosphorylated Tau protein, characteristic of AD pathology. Further, transcriptional analyses demonstrated the differential expression of many genes and cellular pathways, including those associated with synaptic dysfunction. Taken together, the current study demonstrates the ability of retinal organoids to serve as a powerful model for the identification of some of the earliest retinal alterations associated with AD.© 2023. Springer Nature Limited.