Lizama Britney N, Keeling Eloise, Cho Eunah, Malagise Evi M, Knezovich Nicole, Waybright Lora, Watto Emily, Look Gary, Di Caro Valentina, Caggiano Anthony O, Ratnayaka J Arjuna, Hamby Mary E
Cognition Therapeutics Inc., Pittsburgh, PA, USA.
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP806, Tremona Road, Southampton, SO16 6YD, UK.
Sci Rep. 2025 Feb 10;15(1):4256. doi: 10.1038/s41598-025-87921-9.
Trafficking defects in retinal pigmented epithelial (RPE) cells contribute to RPE atrophy, a hallmark of geographic atrophy (GA) in dry age-related macular degeneration (AMD). Dry AMD pathogenesis is multifactorial, including amyloid-β (Aβ) accumulation and oxidative stress-common features of Alzheimer's disease (AD). The Sigma-2 receptor (S2R) regulates lipid and protein trafficking, and S2R modulators reverse trafficking deficits in neurodegeneration in vitro models. Given overlapping mechanisms contributing to AD and AMD, S2R modulator effects on RPE function were investigated. The S2R modulator CT1812 is in clinical trials for AD, dementia with Lewy bodies, and GA. Leveraging AD trials testing CT1812, unbiased analyses of patient biofluid proteomes revealed that proteins altered by CT1812 associated with GA and macular degeneration disease ontologies and overlapped with proteins altered in dry AMD. Differential expression analysis of RPE transcripts from APP-Swedish/London mutant transgenic mice, a model featuring Aβ accumulation, revealed reversal of autophagy/trafficking transcripts in S2R modulator-treated animals versus vehicle toward healthy control levels. Photoreceptor outer segment (POS) trafficking in human RPE cells showed deficits in response to Aβ or hydrogen peroxide compared to vehicle. S2R modulators normalized stressor-induced POS trafficking deficits, resembling healthy control. Taken together, S2R modulation may provide a novel therapeutic strategy for dry AMD.
视网膜色素上皮（RPE）细胞的转运缺陷会导致RPE萎缩，这是干性年龄相关性黄斑变性（AMD）中地图样萎缩（GA）的一个标志。干性AMD的发病机制是多因素的，包括淀粉样β蛋白（Aβ）积累和氧化应激——这是阿尔茨海默病（AD）的常见特征。西格玛-2受体（S2R）调节脂质和蛋白质转运，并且S2R调节剂可逆转体外神经退行性病变模型中的转运缺陷。鉴于AD和AMD存在重叠的发病机制，研究了S2R调节剂对RPE功能的影响。S2R调节剂CT1812正在进行针对AD、路易体痴呆和GA的临床试验。利用测试CT1812的AD试验，对患者生物流体蛋白质组进行的无偏分析表明，被CT1812改变的蛋白质与GA和黄斑变性疾病本体相关，并且与干性AMD中改变的蛋白质重叠。对APP-瑞典/伦敦突变转基因小鼠（一种具有Aβ积累特征的模型）的RPE转录本进行差异表达分析，结果显示，与载体对照相比，在S2R调节剂处理的动物中，自噬/转运转录本恢复到健康对照水平。与载体对照相比，人RPE细胞中的光感受器外段（POS）转运在受到Aβ或过氧化氢刺激时表现出缺陷。S2R调节剂使应激源诱导的POS转运缺陷恢复正常，类似于健康对照。综上所述，S2R调节可能为干性AMD提供一种新的治疗策略。
