Seyed Hosseini Fin Nafiseh, Georgevsky Dana, Sukkar Maria B, Golzan S Mojtaba
Vision Science Group, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.
Pharmacy Discipline, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.
Front Cell Neurosci. 2023 Apr 12;17:1156084. doi: 10.3389/fncel.2023.1156084. eCollection 2023.
Glaucoma is a progressive neurodegenerative disease associated with age. Accumulation of amyloid-beta (Aß) proteins in the ganglion cell layer (GCL) and subsequent retinal ganglion cell (RGC) loss is an established pathological hallmark of the disease. The mechanism through which Aß provokes RGC loss remains unclear. The receptor for the advanced glycation end product (RAGE), and its ligand Aß, have been shown to mediate neuronal loss internalizing Aß within the neurons. In this study, we investigated whether the RAGE-Aß axis plays a role in RGC loss in experimental glaucoma.
Retinal ischemia was induced by an acute elevation of intraocular pressure in RAGE and wild-type (WT) control mice. In a subset of animals, oligomeric Aß was injected directly into the vitreous of both strains. RGC loss was assessed using histology and biochemical assays. Baseline and terminal positive scotopic threshold (pSTR) were also recorded.
Retinal ischemia resulted in 1.9-fold higher RGC loss in WT mice compared to RAGE mice (36 ± 3% < 0.0001 vs. 19 ± 2%, = 0.004). Intravitreal injection of oligomeric Aß resulted in 2.3-fold greater RGC loss in WT mice compared to RAGE mice, 7-days post-injection (55 ± 4% = 0.008 vs. 24 ± 2%, = 0.02). We also found a significant decline in the positive scotopic threshold response (pSTR) amplitude of WT mice compared to RAGE (36 ± 3% vs. 16 ± 6%).
RAGE mice are protected against RGC loss following retinal ischemia. Intravitreal injection of oligomeric Aß accelerated RGC loss in WT mice but not RAGE. A co-localization of RAGE and Aß, suggests that RAGE-Aß binding may contribute to RGC loss.
青光眼是一种与年龄相关的进行性神经退行性疾病。淀粉样β（Aβ）蛋白在神经节细胞层（GCL）中的积累以及随后视网膜神经节细胞（RGC）的丢失是该疾病已确定的病理标志。Aβ引发RGC丢失的机制尚不清楚。晚期糖基化终产物受体（RAGE）及其配体Aβ已被证明可通过使Aβ在神经元内内化来介导神经元丢失。在本研究中，我们调查了RAGE - Aβ轴在实验性青光眼中RGC丢失是否起作用。
通过急性升高RAGE和野生型（WT）对照小鼠的眼压诱导视网膜缺血。在一部分动物中，将寡聚Aβ直接注射到两种品系的玻璃体中。使用组织学和生化分析评估RGC丢失情况。还记录了基线和终末暗视阈值（pSTR）。
与RAGE小鼠相比，视网膜缺血导致WT小鼠的RGC丢失高1.9倍（36±3% < 0.0001对19±2%， = 0.004）。玻璃体腔内注射寡聚Aβ后7天，与RAGE小鼠相比，WT小鼠的RGC丢失高2.3倍（55±4% = 0.008对24±2%， = 0.02）。我们还发现与RAGE相比，WT小鼠的暗视阈值反应（pSTR）幅度显著下降（36±3%对16±6%）。
RAGE小鼠在视网膜缺血后对RGC丢失具有保护作用。玻璃体腔内注射寡聚Aβ加速了WT小鼠而非RAGE小鼠的RGC丢失。RAGE和Aβ的共定位表明，RAGE - Aβ结合可能导致RGC丢失。
