Palacios Adrián G, Zhang Sarah X, Acosta Mónica L
Instituto de Neurociencia and Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaiso, Chile.
Departments of Ophthalmology and Biochemistry, Ross Eye Institute, University at Buffalo, State University of New York, Buffalo, New York, USA.
Alzheimers Dement. 2025 Aug;21(8):e70497. doi: 10.1002/alz.70497.
Diabetic retinopathy (DR) and Alzheimer's disease (AD) are progressive neurodegenerative disorders affecting the eye and the brain, respectively. Despite targeting different organs, they share common molecular mechanisms. A central process connecting these conditions is the unfolded protein response (UPR), which maintains protein homeostasis in the endoplasmic reticulum (ER). Dysregulation of UPR pathways, particularly the IRE1-XBP1 and PERK-eIF2α pathways, can lead to inflammation, oxidative stress, and neurodegeneration. While the IRE1-XBP1 pathway regulates protein folding and inflammatory signaling, the PERK-eIF2α pathway reduces protein synthesis but may trigger apoptosis if persistently activated. Emerging therapies targeting UPR pathways and ER chaperones show promise in mitigating neurodegenerative damage in DR and AD. This review highlights shared pathophysiological mechanisms, explore retinal biomarkers for early AD detection, and emphasizes UPR modulation as a therapeutic strategy for neurodegeneration in aging-related diseases. HIGHLIGHTS: Diabetic retinopathy (DR, ocular disorder) and Alzheimer's disease (AD, cerebral disorder) share common molecular mechanisms, including oxidative stress, inflammation, and proteostasis dysfunction. UPR is a critical pathway linking both diseases through endoplasmic reticulum (ER) stress and neurodegeneration and targeting unfolded protein response (UPR) pathways, ER chaperones (e.g., P58IPK), and anti-inflammatory treatments show promise. The IRE1-XBP1 pathway regulates protein homeostasis and inflammation; XBP1s protects against ER stress in both retinal and brain neurons. The PERK-eIF2α pathway suppresses protein synthesis under stress but may induce apoptosis via ATF4 and CHOP if chronically activated. Age-related decline in metabolism, proteostasis, and neurovascular function intensifies disease progression and exacerbates molecular and cellular damage in both DR and AD.
糖尿病性视网膜病变（DR）和阿尔茨海默病（AD）分别是影响眼睛和大脑的进行性神经退行性疾病。尽管它们针对不同器官，但具有共同的分子机制。连接这些病症的一个核心过程是未折叠蛋白反应（UPR），它在内质网（ER）中维持蛋白质稳态。UPR途径的失调，特别是IRE1-XBP1和PERK-eIF2α途径，可导致炎症、氧化应激和神经退行性变。虽然IRE1-XBP1途径调节蛋白质折叠和炎症信号传导，但PERK-eIF2α途径会减少蛋白质合成，但如果持续激活可能会引发细胞凋亡。针对UPR途径和内质网伴侣的新兴疗法在减轻DR和AD中的神经退行性损伤方面显示出前景。本综述强调了共同的病理生理机制，探索用于早期AD检测的视网膜生物标志物，并强调UPR调节作为衰老相关疾病中神经退行性变的治疗策略。要点：糖尿病性视网膜病变（DR，眼部疾病）和阿尔茨海默病（AD，脑部疾病）具有共同的分子机制，包括氧化应激、炎症和蛋白质稳态功能障碍。UPR是通过内质网（ER）应激和神经退行性变将这两种疾病联系起来的关键途径，针对未折叠蛋白反应（UPR）途径、内质网伴侣（如P58IPK）和抗炎治疗显示出前景。IRE1-XBP1途径调节蛋白质稳态和炎症；XBP1s保护视网膜和脑神经元免受内质网应激。PERK-eIF2α途径在应激下抑制蛋白质合成，但如果长期激活可能通过ATF4和CHOP诱导细胞凋亡。与年龄相关的代谢、蛋白质稳态和神经血管功能下降会加剧疾病进展，并加重DR和AD中的分子和细胞损伤。
