Cholesterol Accumulation Promotes Photoreceptor Senescence and Retinal Degeneration.

IF 5 2区医学 Q1 OPHTHALMOLOGY Investigative ophthalmology & visual science Pub Date : 2024-08-01 DOI:10.1167/iovs.65.10.29

Ryo Terao, Brian S Sohn, Taku Yamamoto, Tae Jun Lee, Jason Colasanti, Charles W Pfeifer, Joseph B Lin, Andrea Santeford, Shinobu Yamaguchi, Mitsukuni Yoshida, Rajendra S Apte

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Abstract

Purpose: Dysregulated cholesterol metabolism is critical in the pathogenesis of AMD. Cellular senescence contributes to the development of numerous age-associated diseases. In this study, we investigated the link between cholesterol burden and the cellular senescence of photoreceptors.

Methods: Retinas from rod-specific ATP binding cassette subfamily A member 1 (Abca1) and G member 1 (Abcg1) (Abca1/g1-rod/-rod) knockout mice fed with a high-fat diet were analyzed for the signs of cellular senescence. Real-time quantitative PCR and immunofluorescence were used to characterize the senescence profile of the retina and cholesterol-treated photoreceptor cell line (661W). Inducible elimination of p16(Ink4a)-positive senescent cells (INK-ATTAC) mice or the administration of senolytic drugs (dasatinib and quercetin: D&Q) were used to examine the impact of senolytics on AMD-like phenotypes in Abca1/g1-rod/-rod retina.

Results: Increased accumulation of senescent cells as measured by markers of cellular senescence was found in Abca1/g1-rod/-rod retina. Exogenous cholesterol also induced cellular senescence in 661W cells. Selective elimination of senescent cells in Abca1/g1-rod/-rod;INK-ATTAC mice or by administration of D&Q improved visual function, lipid accumulation in retinal pigment epithelium, and Bruch's membrane thickening.

Conclusions: Cholesterol accumulation promotes cellular senescence in photoreceptors. Eliminating senescent photoreceptors improves visual function in a model of retinal neurodegeneration, and senotherapy offers a novel therapeutic avenue for further investigation.

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胆固醇积累促进光感受器衰老和视网膜退化

目的：胆固醇代谢失调在老年性黄斑变性的发病机制中至关重要。细胞衰老会导致许多与年龄相关疾病的发生。在这项研究中，我们调查了胆固醇负担与感光细胞衰老之间的联系：方法：分析了以高脂饮食喂养的杆特异性 ATP 结合盒亚族 A 成员 1（Abca1）和 G 成员 1（Abcg1）（Abca1/g1-rod/-rod）基因敲除小鼠的视网膜，以发现细胞衰老的迹象。实时定量 PCR 和免疫荧光被用来描述视网膜和胆固醇处理的感光细胞系（661W）的衰老特征。诱导性消除p16(Ink4a)阳性衰老细胞（INK-ATTAC）小鼠或服用衰老药物（达沙替尼和槲皮素：D&Q）被用来研究衰老药物对Abca1/g1-rod/-rod视网膜中AMD样表型的影响：结果：根据细胞衰老标志物的测量，Abca1/g1-rod/-rod 视网膜中衰老细胞的积累增加。外源性胆固醇也诱导了 661W 细胞的衰老。选择性地消除 Abca1/g1-rod/rod;INK-ATTAC 小鼠的衰老细胞或服用 D&Q 可改善视功能、视网膜色素上皮的脂质积累和布鲁氏膜增厚：结论：胆固醇积累会促进感光细胞的衰老。消除衰老的感光细胞可改善视网膜神经变性模型的视觉功能，而衰老疗法为进一步研究提供了一条新的治疗途径。

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来源期刊

Investigative ophthalmology & visual science 医学-眼科学

CiteScore

6.90

自引率

4.50%

发文量

339

审稿时长

1 months

期刊介绍： Investigative Ophthalmology & Visual Science (IOVS), published as ready online, is a peer-reviewed academic journal of the Association for Research in Vision and Ophthalmology (ARVO). IOVS features original research, mostly pertaining to clinical and laboratory ophthalmology and vision research in general.