Abhyankar Surabhi D, Luo Qianyi, Hartman Gabriella D, Mahajan Neha, Corson Timothy W, Oblak Adrian L, Lamb Bruce T, Bhatwadekar Ashay D
Department of Ophthalmology, Indiana University School of Medicine, GK-310, 1160 W Michigan Street, Indianapolis, Indiana, US-46202.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Medical Sciences Building, Room 4053, 635 Barnhill Drive, Indianapolis, Indiana, US-46202.
bioRxiv. 2025 Aug 1:2025.07.30.667671. doi: 10.1101/2025.07.30.667671.
The genotype influences metabolic and neurodegenerative outcomes, with carriers at higher risk for Alzheimer's disease (AD) and metabolic dysfunction. This study examines how long-term dietary interventions affect systemic metabolism, retinal structure/function in -knock-in (KI, neutral for AD) and -KI mice. Humanized and -KI mice received either a control diet (CD) or a Western diet (WD) for 2, 6, or 12 months. Body weight, glucose metabolism, lipid profiles, retinal structure, function, vasculature, visual performance, and inflammatory markers were analyzed. WD induced early glucose intolerance in mice (2 months); mice showed impairment only after prolonged exposure (6-12 months). Notably, WD-fed mice exhibited more pronounced hyperlipidemia than mice. CD mice displayed early retinal thinning (6 months), while WD mice initially exhibited retinal swelling, followed by degeneration (12 months). WD exacerbated retinal vascular dysfunction in mice, with increased tortuosity and reduced vascular area. Elevated expression in WD-fed mice confirmed inflammation-associated retinal dysfunction. mice showed heightened vulnerability to diet, with WD worsening metabolic, retinal, and vascular impairments. While CD improved glucose metabolism, it did not prevent retinal dysfunction. These findings underscore genotype-specific dietary strategies to mitigate -associated risks.
基因型影响代谢和神经退行性病变的结果，携带者患阿尔茨海默病（AD）和代谢功能障碍的风险更高。本研究探讨长期饮食干预如何影响全身代谢、视网膜结构/功能，研究对象为基因敲入（KI，对AD呈中性）小鼠和基因敲除KI小鼠。人源化小鼠和KI小鼠分别接受对照饮食（CD）或西式饮食（WD）2、6或12个月。分析了体重、葡萄糖代谢、血脂谱、视网膜结构、功能、脉管系统、视觉表现和炎症标志物。WD在小鼠中诱导早期葡萄糖不耐受（2个月）；KI小鼠仅在长期暴露后（6 - 12个月）出现损伤。值得注意的是，喂食WD的KI小鼠比KI小鼠表现出更明显的高脂血症。CD喂养的KI小鼠在6个月时出现早期视网膜变薄，而WD喂养的KI小鼠最初表现为视网膜肿胀，随后发生退化（12个月）。WD加剧了KI小鼠的视网膜血管功能障碍，表现为迂曲增加和血管面积减小。WD喂养的KI小鼠中表达升高证实了与炎症相关的视网膜功能障碍。KI小鼠对饮食表现出更高的易感性，WD会加重代谢、视网膜和血管损伤。虽然CD改善了葡萄糖代谢，但并不能预防视网膜功能障碍。这些发现强调了针对特定基因型的饮食策略以减轻相关风险。
