Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
MD-Powell Gene Therapy Center, University of Florida, Gainesville, FL 32611, USA.
Mol Ther. 2023 Jul 5;31(7):2042-2055. doi: 10.1016/j.ymthe.2023.03.029. Epub 2023 Apr 3.
We reported previously that β-site amyloid precursor protein cleaving enzyme (BACE1) is strongly expressed in the normal retina and that BACE1 mice develop pathological phenotypes associated with age-related macular degeneration (AMD). BACE1 expression is increased within the neural retina and retinal pigment epithelium (RPE) in AMD donor eyes suggesting that increased BACE1 is compensatory. We observed that AAV-mediated BACE1 overexpression in the RPE was maintained up to 6 months after AAV1-BACE1 administration. No significant changes in normal mouse visual function or retinal morphology were observed with low-dose vector while the high-dose vector demonstrated some early pathology which regressed with time. No increase in β-amyloid was observed. BACE1 overexpression in the RPE of the superoxide dismutase 2 knockdown (SOD2 KD) mouse, which exhibits an AMD-like phenotype, prevented loss of retinal function and retinal pathology, and this was sustained out to 6 months. Furthermore, BACE1 overexpression was able to inhibit oxidative stress, microglial changes, and loss of RPE tight junction integrity (all features of AMD) in SOD2 KD mice. In conclusion, BACE1 plays a key role in retina/RPE homeostasis, and BACE1 overexpression offers a novel therapeutic target in the treatment of AMD.
我们之前曾报道过β-淀粉样前体蛋白裂解酶（BACE1）在正常视网膜中表达强烈，而 BACE1 小鼠则会出现与年龄相关性黄斑变性（AMD）相关的病理表型。在 AMD 供体眼中，神经视网膜和视网膜色素上皮（RPE）中的 BACE1 表达增加，表明 BACE1 的增加是代偿性的。我们观察到，RPE 中的 AAV 介导的 BACE1 过表达在 AAV1-BACE1 给药后可维持长达 6 个月。低剂量载体对正常小鼠的视觉功能或视网膜形态没有明显影响，而高剂量载体则显示出一些早期病理，随着时间的推移会消退。没有观察到β-淀粉样蛋白的增加。在超氧化物歧化酶 2 敲低（SOD2 KD）小鼠的 RPE 中过表达 BACE1，该小鼠表现出类似于 AMD 的表型，可防止视网膜功能和视网膜病理的丧失，这种情况可持续到 6 个月。此外，BACE1 过表达能够抑制 SOD2 KD 小鼠中的氧化应激、小胶质细胞变化和 RPE 紧密连接完整性的丧失（AMD 的所有特征）。总之，BACE1 在视网膜/RPE 稳态中发挥着关键作用，BACE1 过表达为 AMD 的治疗提供了一个新的治疗靶点。
