Visual changes are some of the earliest symptoms that patients with Alzheimer’s disease (AD) experience. Pathophysiological processes such as amyloid-β plaque formation, vascular changes, neuroinflammation, and loss of retinal ganglion cells (RGCs) have been detected in the retina of AD patients and animal models. However, little is known about the molecular processes that underlie retinal neurodegeneration in AD. The cellular architecture and constant sensory activity of the retina impose high metabolic demands. We thus hypothesized that energy metabolism might be compromised in the AD retina similarly to what has been observed in the AD brain. To address this question, we explored cellular alterations and retinal metabolic activity in the 5 × FAD mouse model of AD. We used 8-month-old female 5 × FAD mice, in which the AD-related pathology has been shown to be apparent. We observed that RGC density is selectively affected in the retina of 5 × FAD mice. To map retinal metabolic activity, we incubated isolated retinal tissue with [U-¹³C] glucose and analyzed tissue extracts by gas chromatography-mass spectrometry. We found that the retinas of 5 × FAD mice exhibit glucose hypometabolism. Moreover, we detected decreased glutamine synthesis in 5 × FAD retinas but no changes in the expression of markers of Müller glia, the main glial cell type responsible for glutamate uptake and glutamine synthesis in the retina. These findings suggest that AD presents with metabolic alterations not only in the brain but also in the retina that may be detrimental to RGC activity and survival, potentially leading to the visual impairments that AD patients suffer.

视觉变化是阿尔茨海默病 (AD) 患者最早出现的一些症状。已在 AD 患者和动物模型的视网膜中检测到诸如淀粉样蛋白-β 斑块形成​​、血管变化、神经炎症和视网膜神经节细胞 (RGC) 缺失等病理生理过程。然而，关于 AD 中视网膜神经变性的分子过程知之甚少。视网膜的细胞结构和持续的感觉活动对代谢提出了很高的要求。因此，我们假设 AD 视网膜中的能量代谢可能会受到损害，类似于在 AD 大脑中观察到的情况。为了解决这个问题，我们探索了 AD 的 5 × FAD 小鼠模型中的细胞改变和视网膜代谢活动。我们使用了 8 个月大的雌性 5 × FAD 小鼠，其中与 AD 相关的病理学已被证明是明显的。我们观察到 RGC 密度在 5 × FAD 小鼠的视网膜中受到选择性影响。为了绘制视网膜代谢活动图，我们将分离的视网膜组织与 [U-¹³ C]葡萄糖和通过气相色谱-质谱分析的组织提取物。我们发现 5 × FAD 小鼠的视网膜表现出葡萄糖低代谢。此外，我们检测到 5 × FAD 视网膜中谷氨酰胺合成减少，但 Müller 胶质细胞标志物的表达没有变化，Müller 胶质细胞是视网膜中负责谷氨酸摄取和谷氨酰胺合成的主要胶质细胞类型。这些发现表明，AD 不仅在大脑中而且在视网膜中都出现代谢改变，这可能不利于 RGC 活动和存活，可能导致 AD 患者遭受视力障碍。