Aier School of Ophthalmology, Central South University, Changsha, Hunan, China.
Aier Eye Institute, Changsha, Hunan, China.
Cell Mol Neurobiol. 2022 Nov;42(8):2893-2907. doi: 10.1007/s10571-021-01160-w. Epub 2021 Oct 26.
Aging is a risk factor for multiple retinal degeneration diseases. Entraining brain gamma oscillations with gamma-flicker light (γFL) has been confirmed to coordinate pathological changes in several Alzheimer's disease mouse models and aged mice. However, the direct effect of γFL on retinal aging remains unknown. We assessed retinal senescence-associated beta-galactosidase (β-gal) and autofluorescence in 20-month-old mice and found reduced β-gal-positive cells in the inner retina and diminished lipofuscin accumulation around retinal vessels after 6 days of γFL. In immunofluorescence, γFL was further demonstrated to ameliorate aging-related retinal changes, including a decline in microtubule-associated protein 1 light chain 3 beta expression, an increase in complement C3 activity, and an imbalance between the anti-oxidant factor catalase and pro-oxidant factor carboxymethyl lysine. Moreover, we found that γFL can increase the expression of activating transcription factor 4 (ATF4) in the inner retina, while revealing a decrease of ATF4 expression in the inner retina and positive expression in the outer segment of photoreceptor and RPE layer for aged mice. Western blotting was then used to confirm the immunofluorescence results. After mRNA sequencing (NCBI Sequence Read Archive database: PRJNA748184), we found several main mechanistic clues, including mitochondrial function and chaperone-mediated protein folding. Furthermore, we extended γFL to aged Apoe mice and showed that 1-m γFL treatment even improved the structures of retinal-pigment-epithelium basal infolding and Bruch's membrane. Overall, γFL can orchestrate various pathological characteristics of retinal aging in mice and might be a noninvasive, convenient, and tissue-specific therapeutic strategy for retinal aging.
衰老是多种视网膜变性疾病的一个风险因素。用伽马闪烁光（γFL）使大脑伽马振荡同步已被证实可协调几种阿尔茨海默病小鼠模型和老年小鼠的病理变化。然而，γFL 对视网膜衰老的直接影响尚不清楚。我们评估了 20 月龄小鼠的视网膜衰老相关的β-半乳糖苷酶（β-gal）和自发荧光，发现经过 6 天的 γFL 后，内视网膜中β-gal 阳性细胞减少，视网膜血管周围脂褐素积累减少。在免疫荧光中，γFL 进一步改善了与衰老相关的视网膜变化，包括微管相关蛋白 1 轻链 3β表达下降、补体 C3 活性增加以及抗氧化因子过氧化氢酶和促氧化剂羧甲基赖氨酸之间的失衡。此外，我们发现 γFL 可以增加内视网膜中激活转录因子 4（ATF4）的表达，而在老年小鼠中，内视网膜 ATF4 表达减少，外节光感受器和 RPE 层 ATF4 表达阳性。然后用 Western blot 验证免疫荧光结果。通过 mRNA 测序（NCBI Sequence Read Archive 数据库：PRJNA748184），我们发现了几个主要的机制线索，包括线粒体功能和伴侣介导的蛋白质折叠。此外，我们将 γFL 扩展到老年 Apoe 小鼠，并表明 1-m γFL 处理甚至改善了视网膜色素上皮基底内陷和布鲁赫膜的结构。总之，γFL 可以协调小鼠视网膜衰老的各种病理特征，可能是一种非侵入性、方便和组织特异性的治疗视网膜衰老的策略。
