Cao Kevin J, Kim John H, Kroeger Heike, Gaffney Patricia M, Lin Jonathan H, Sigurdson Christina J, Yang Jerry
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
Departments of Pathology and Medicine, University of California, San Diego, La Jolla, CA, USA.
Transl Vis Sci Technol. 2021 Jun 1;10(7):5. doi: 10.1167/tvst.10.7.5.
To investigate the use of an amyloid-targeting fluorescent probe, ARCAM-1, to identify amyloid-containing deposits in the retina of a transgenic mouse model of Alzheimer's disease (AD) and in human postmortem AD patients.
Aged APP/PS1 transgenic AD and wild-type (WT) mice were given an intraperitoneal (IP) injection of ARCAM-1 and their retinas imaged in vivo using a fluorescence ophthalmoscope. Eyes were enucleated and dissected for ex vivo inspection of retinal amyloid deposits. Additionally, formalin-fixed eyes from human AD and control patients were dissected, and the retinas were stained using ARCAM-1 or with an anti-amyloid-β antibody. Confocal microscopy was used to image amyloid-containing deposits stained with ARCAM-1 or with immunostaining.
Four out of eight APP/PS1 mice showed the presence of amyloid aggregates in the retina during antemortem imaging. Retinas from three human AD patients stained with ARCAM-1 showed an apparent increased density of fluorescently labeled amyloid-containing deposits compared to the retinas from two healthy, cognitively normal (CN) patients. Immunolabeling confirmed the presence of amyloid deposits in both the retinal neuronal layers and in retinal vasculature.
ARCAM-1 facilitates antemortem detection of amyloid aggregates in the retina of a mouse model for AD, and postmortem detection of amyloid-containing deposits in human retinal tissues from AD patients. These results support the hypothesis of AD pathology manifesting in the eye and highlight a novel area for fluorophore development for the optical detection of retinal amyloid in AD patients.
This paper represents an initial examination for potential translation of an amyloid-targeting fluorescent probe to a retinal imaging agent for aiding in the diagnosis of Alzheimer's disease.
研究一种靶向淀粉样蛋白的荧光探针ARCAM-1在阿尔茨海默病（AD）转基因小鼠模型视网膜以及AD患者死后视网膜中识别含淀粉样蛋白沉积物的应用。
对老年APP/PS1转基因AD小鼠和野生型（WT）小鼠进行腹腔注射ARCAM-1，然后使用荧光检眼镜对其视网膜进行活体成像。摘除眼球并解剖以对视网膜淀粉样蛋白沉积物进行离体检查。此外，对来自AD患者和对照患者的福尔马林固定眼球进行解剖，并用ARCAM-1或抗淀粉样β抗体对视网膜进行染色。共聚焦显微镜用于对用ARCAM-1染色或免疫染色的含淀粉样蛋白沉积物进行成像。
在生前成像期间，8只APP/PS1小鼠中有4只视网膜中存在淀粉样蛋白聚集体。与2名健康的认知正常（CN）患者的视网膜相比，用ARCAM-1染色的3名AD患者的视网膜显示荧光标记的含淀粉样蛋白沉积物密度明显增加。免疫标记证实视网膜神经元层和视网膜血管中均存在淀粉样蛋白沉积物。
ARCAM-1有助于在AD小鼠模型视网膜中进行生前淀粉样蛋白聚集体检测，以及在AD患者的人视网膜组织中进行死后含淀粉样蛋白沉积物检测。这些结果支持AD病理在眼部表现的假说，并突出了用于AD患者视网膜淀粉样蛋白光学检测的新型荧光团开发领域。
本文代表了将一种靶向淀粉样蛋白的荧光探针潜在转化为用于辅助阿尔茨海默病诊断视网膜成像剂的初步研究。
