Liu Jian, Yi Caijiao, Qi Jinyan, Cui Xuexue, Yuan Xiangling, Deng Wen, Chen Mei, Xu Heping
Aier Academy of Ophthalmology, Central South University, Changsha, Hunan, China.
Aier Eye Institute, Changsha Aier Eye Hospital, Changsha, Hunan, China.
Aging Cell. 2025 Sep;24(9):e70161. doi: 10.1111/acel.70161. Epub 2025 Jul 13.
Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocular translocation of bacteria from the blood circulation are critically involved in retinal degeneration. We hypothesise that the blood-retinal barrier (BRB) cells can protect the neuroretina from blood-borne pathogens by producing antimicrobial peptides (AMPs). The antimicrobial activity may decline during ageing, putting the retina at risk of low-degree chronic inflammation and degeneration. Here, we found that the retinal pigment epithelial (RPE) cells, which form the outer BRB, express a variety of AMPs/AMP precursors, including APP, RARRES2, FAM3A, HAMP, CAMP, GNLY, and PI3. Senescent RPE cells expressed lower levels of APP and RARRES2 mRNA, accompanied by increased intracellular retention of E. coli in a bactericidal assay. Silencing APP, not RARRES2, with shRNA reduced the antibacterial activity of RPE cells. Senescent RPE cells had lower levels of α-secretase and higher levels of β-secretase (BACE1) and γ-secretase (PS1), accompanied by reduced soluble APPα and increased amyloid beta (Aβ) production, particularly the Aβ42 isoform. Eyes from aged donors showed a higher Aβ accumulation within RPE cells. Our results suggest that while RPE cells possess antimicrobial activity, this ability declines with age and is impaired in senescent cells. The impaired antimicrobial activity and augmented Aβ deposition in senescent RPE cells may contribute to age-related retinal para-inflammation and neurodegeneration.
年龄相关性视网膜变性，如糖尿病性视网膜病变和年龄相关性黄斑变性，是现代社会失明的主要原因。最近的研究表明，微生物群落失调以及细菌从血液循环向眼内的转移与视网膜变性密切相关。我们推测血视网膜屏障（BRB）细胞可通过产生抗菌肽（AMP）来保护神经视网膜免受血源性病原体的侵害。随着年龄增长，抗菌活性可能会下降，使视网膜面临低度慢性炎症和变性的风险。在此，我们发现构成外BRB的视网膜色素上皮（RPE）细胞表达多种AMP/AMP前体，包括APP、RARRES2、FAM3A、HAMP、CAMP、GNLY和PI3。衰老的RPE细胞中APP和RARRES2 mRNA表达水平较低，在杀菌试验中，细胞内大肠杆菌的滞留量增加。用短发夹RNA（shRNA）沉默APP而非RARRES2可降低RPE细胞的抗菌活性。衰老的RPE细胞中α-分泌酶水平较低，β-分泌酶（BACE1）和γ-分泌酶（PS1）水平较高，同时可溶性APPα减少，淀粉样β蛋白（Aβ）生成增加，尤其是Aβ42亚型。老年供体的眼睛在RPE细胞内显示出更高的Aβ积累。我们的结果表明，虽然RPE细胞具有抗菌活性，但这种能力会随着年龄增长而下降，并且在衰老细胞中受损。衰老RPE细胞中受损的抗菌活性和增加的Aβ沉积可能导致年龄相关性视网膜旁炎症和神经变性。
