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胆固醇积累促进光感受器衰老和视网膜变性。

Cholesterol Accumulation Promotes Photoreceptor Senescence and Retinal Degeneration.

机构信息

John F. Hardesty, MD, Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States.

Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.

出版信息

Invest Ophthalmol Vis Sci. 2024 Aug 1;65(10):29. doi: 10.1167/iovs.65.10.29.

DOI:10.1167/iovs.65.10.29
PMID:39167399
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11343002/
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.

摘要

目的

胆固醇代谢失调在 AMD 的发病机制中起着关键作用。细胞衰老导致许多与年龄相关的疾病的发生。在这项研究中，我们研究了胆固醇负担与光感受器细胞衰老之间的联系。

方法

用高脂肪饮食喂养 rod-specific ATP binding cassette subfamily A member 1（Abca1）和 G member 1（Abcg1）（Abca1/g1-rod/-rod）敲除小鼠的视网膜，并分析其细胞衰老的迹象。实时定量 PCR 和免疫荧光用于描述视网膜和胆固醇处理的光感受器细胞系（661W）的衰老特征。诱导性消除 p16(Ink4a)-阳性衰老细胞（INK-ATTAC）小鼠或使用衰老细胞清除药物（达沙替尼和槲皮素：D&Q）来检查衰老细胞清除对 Abca1/g1-rod/-rod 视网膜中 AMD 样表型的影响。

结果

通过细胞衰老标志物测量，在 Abca1/g1-rod/-rod 视网膜中发现衰老细胞的积累增加。外源性胆固醇也诱导 661W 细胞发生细胞衰老。Abca1/g1-rod/-rod;INK-ATTAC 小鼠中衰老细胞的选择性消除或 D&Q 的给药改善了视觉功能、视网膜色素上皮中的脂质积累和 Bruch 膜增厚。

结论

胆固醇积累促进光感受器细胞的衰老。消除衰老的光感受器可改善视网膜神经退行性变模型中的视觉功能，衰老细胞治疗为进一步研究提供了新的治疗途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/ebc7905b4eb5/iovs-65-10-29-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/83bda2ec40e7/iovs-65-10-29-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/47fc93560641/iovs-65-10-29-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/075f9f5681f2/iovs-65-10-29-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/9d9e73eb6b2e/iovs-65-10-29-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/ebc7905b4eb5/iovs-65-10-29-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/83bda2ec40e7/iovs-65-10-29-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/47fc93560641/iovs-65-10-29-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/075f9f5681f2/iovs-65-10-29-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/9d9e73eb6b2e/iovs-65-10-29-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baee/11343002/ebc7905b4eb5/iovs-65-10-29-f005.jpg

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