Extensive effort has been made studying retinal pathology in Alzheimer’s disease (AD) to improve early noninvasive diagnosis and treatment. Particularly relevant are vascular changes, which appear prominent in early brain pathogenesis and could predict cognitive decline. Recently, we identified platelet-derived growth factor receptor beta (PDGFRβ) deficiency and pericyte loss associated with vascular Aβ deposition in the neurosensory retina of mild cognitively impaired (MCI) and AD patients. However, the pathological mechanisms of retinal vascular changes and their possible relationships with vascular amyloidosis, pericyte loss, and blood-retinal barrier (BRB) integrity remain unknown. Here, we evaluated the retinas of transgenic APPSWE/PS1ΔE9 mouse models of AD (ADtg mice) and wild-type mice at different ages for capillary degeneration, PDGFRβ expression, vascular amyloidosis, permeability and inner BRB tight-junction molecules. Using a retinal vascular isolation technique followed by periodic acid-Schiff or immunofluorescent staining, we discovered significant retinal capillary degeneration in ADtg mice compared to age- and sex-matched wild-type mice (P < 0.0001). This small vessel degeneration reached significance in 8-month-old mice (P = 0.0035), with males more susceptible than females. Degeneration of retinal capillaries also progressively increased with age in healthy mice (P = 0.0145); however, the phenomenon was significantly worse during AD-like progression (P = 0.0001). A substantial vascular PDGFRβ deficiency (~ 50% reduction, P = 0.0017) along with prominent vascular Aβ deposition was further detected in the retina of ADtg mice, which inversely correlated with the extent of degenerated capillaries (Pearson’s r = − 0.8, P = 0.0016). Importantly, tight-junction alterations such as claudin-1 downregulation and increased BRB permeability, demonstrated in vivo by retinal fluorescein imaging and ex vivo following injection of FITC-dextran (2000 kD) and Texas Red-dextran (3 kD), were found in ADtg mice. Overall, the identification of age- and Alzheimer’s-dependent retinal capillary degeneration and compromised BRB integrity starting at early disease stages in ADtg mice could contribute to the development of novel targets for AD diagnosis and therapy.

中文翻译：

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阿尔茨海默病小鼠模型的视网膜毛细血管变性和血-视网膜屏障破坏

已经为研究阿尔茨海默病 (AD) 的视网膜病理做出了广泛的努力，以改善早期的无创诊断和治疗。特别相关的是血管变化，这在早期脑发病机制中显得突出，可以预测认知能力下降。最近，我们发现了与轻度认知障碍 (MCI) 和 AD 患者的神经感觉视网膜中血管 Aβ 沉积相关的血小板衍生生长因子受体β (PDGFRβ) 缺陷和周细胞丢失。然而，视网膜血管变化的病理机制及其与血管淀粉样变性、周细胞丢失和血-视网膜屏障 (BRB) 完整性的可能关系仍然未知。在这里，我们评估了不同年龄的 AD 转基因 APPSWE/PS1ΔE9 小鼠模型（ADtg 小鼠）和野生型小鼠的视网膜毛细血管变性，PDGFRβ 表达、血管淀粉样变性、通透性和内部 BRB 紧密连接分子。使用视网膜血管分离技术，然后是高碘酸-希夫或免疫荧光染色，我们发现与年龄和性别匹配的野生型小鼠相比，ADtg 小鼠的视网膜毛细血管显着变性（P < 0.0001）。这种小血管变性在 8 个月大的小鼠中达到显着性 (P = 0.0035)，雄性比雌性更易感。在健康小鼠中，视网膜毛细血管的退化也随着年龄的增长而逐渐增加（P = 0.0145）；然而，这种现象在 AD 样进展期间明显更糟（P = 0.0001）。在 ADtg 小鼠的视网膜中进一步检测到大量血管 PDGFRβ 缺乏（减少约 50%，P = 0.0017）以及显着的血管 Aβ 沉积，与退化毛细血管的程度呈负相关（Pearson r = − 0.8，P = 0.0016）。重要的是，通过视网膜荧光素成像在体内和在注射 FITC-葡聚糖（2000 kD）和德克萨斯红-葡聚糖（3 kD）后在体外证明了紧密连接的改变，例如 claudin-1 下调和 BRB 通透性增加，发现于ADtg 小鼠。总体而言，在 ADtg 小鼠的早期疾病阶段发现年龄和阿尔茨海默氏症依赖性视网膜毛细血管变性和 BRB 完整性受损可能有助于开发 AD 诊断和治疗的新靶点。在 ADtg 小鼠中发现了通过视网膜荧光素成像在体内和注射 FITC-葡聚糖（2000 kD）和德克萨斯红-葡聚糖（3 kD）后的离体。总体而言，在 ADtg 小鼠的早期疾病阶段发现年龄和阿尔茨海默氏症依赖性视网膜毛细血管变性和 BRB 完整性受损可能有助于开发 AD 诊断和治疗的新靶点。在 ADtg 小鼠中发现了通过视网膜荧光素成像在体内和注射 FITC-葡聚糖（2000 kD）和德克萨斯红-葡聚糖（3 kD）后的离体。总体而言，在 ADtg 小鼠的早期疾病阶段发现年龄和阿尔茨海默氏症依赖性视网膜毛细血管变性和 BRB 完整性受损可能有助于开发 AD 诊断和治疗的新靶点。