Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
Massachusetts General Hospital Center for Cancer Research, Department of Cell Biology, Harvard Medical School, Charlestown, MA 02129, USA.
Mol Ther. 2021 Jul 7;29(7):2281-2293. doi: 10.1016/j.ymthe.2021.03.014. Epub 2021 Mar 17.
Abnormal cholesterol/lipid homeostasis is linked to neurodegenerative conditions such as age-related macular degeneration (AMD), which is a leading cause of blindness in the elderly. The most prevalent form, termed "dry" AMD, is characterized by pathological cholesterol accumulation beneath the retinal pigment epithelial (RPE) cell layer and inflammation-linked degeneration in the retina. We show here that the cholesterol-regulating microRNA miR-33 was elevated in the RPE of aging mice. Expression of the miR-33 target ATP-binding cassette transporter (ABCA1), a cholesterol efflux pump genetically linked to AMD, declined reciprocally in the RPE with age. In accord, miR-33 modulated ABCA1 expression and cholesterol efflux in human RPE cells. Subcutaneous delivery of miR-33 antisense oligonucleotides (ASO) to aging mice and non-human primates fed a Western-type high fat/cholesterol diet resulted in increased ABCA1 expression, decreased cholesterol accumulation, and reduced immune cell infiltration in the RPE cell layer, accompanied by decreased pathological changes to RPE morphology. These findings suggest that miR-33 targeting may decrease cholesterol deposition and ameliorate AMD initiation and progression.
胆固醇/脂质代谢异常与神经退行性疾病有关，如年龄相关性黄斑变性（AMD），这是老年人失明的主要原因。最常见的形式，称为“干性”AMD，其特征是视网膜色素上皮（RPE）细胞层下的病理性胆固醇积累和与炎症相关的视网膜变性。我们在这里表明，胆固醇调节 microRNA miR-33 在衰老小鼠的 RPE 中升高。miR-33 的靶标 ATP 结合盒转运蛋白（ABCA1）的表达随着年龄的增长在 RPE 中呈反式下降，ABCA1 是一种与 AMD 遗传相关的胆固醇外排泵。同样，miR-33 调节人 RPE 细胞中的 ABCA1 表达和胆固醇外排。向衰老小鼠和用西方型高脂肪/高胆固醇饮食喂养的非人类灵长类动物皮下递送 miR-33 反义寡核苷酸（ASO），导致 ABCA1 表达增加、胆固醇积累减少和 RPE 细胞层中免疫细胞浸润减少，同时 RPE 形态的病理变化减少。这些发现表明，miR-33 的靶向作用可能减少胆固醇沉积，并改善 AMD 的起始和进展。
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