Department of Ophthalmology and Visual Neurosciences, University of Texas Medical Branch, Galveston, TX, USA.
School of Medicine, University of Texas Medical Branch, Galveston, TX, USA.
Exp Eye Res. 2022 Jan;214:108879. doi: 10.1016/j.exer.2021.108879. Epub 2021 Dec 10.
The influence of Alzheimer's disease (AD) progression and severity on the structural and functional integrity of the cerebral vasculature is well recognized. The retina is an extension of the brain; thus, changes in retinal vascular features may serve as markers of AD cerebrovascular pathologies. However, differentiating normal aging-versus AD-induced retinal vascular changes is unresolved. Therefore, we compared and quantified changes in superficial (SVP), intermediate (IVP), and deep (DVP) retinal vascular plexuses in young, middle-age, and old triple transgenic mouse model of AD (3xT-AD) to the changes that occur in age-matched controls (C57BL/6j). We used immunostaining combined with a novel tissue optical clearing approach along with a computational tool for quantitative analysis of vascular network alterations (vessel length and density) in SVP, IVP, and DVP. All three layers had comparable structural features and densities in young 3xTg-AD and control animals. In controls, IVP and DVP densities decreased with aging (-14% to -32% change from young to old, p < 0.05), while no changes were observed in SVP. In contrast, vascular parameters in the transgenic group decreased in all three layers with aging (-12% to -49% change from young to old, p < 0.05). Furthermore, in the old group, SVP and DVP vascular parameters were lower in the transgenics compared to age-matched controls (p < 0.05). Our analysis demonstrates that normal aging and progression of AD lead to various degrees of vascular alterations in the retina. Specifically, compared to normal aging, changes in vascular features of SVP and DVP regions of the retina are accelerated during AD progression. Considering recent advances in the field of depth-resolved imaging of retinal capillary network and microangiography, noninvasive quantitative monitoring of changes in retinal vascular network parameters of SVP and DVP may serve as markers for diagnosis and staging of Alzheimer's disease and discriminating AD-induced vascular attenuation from age-related vasculopathy.
阿尔茨海默病（AD）的进展和严重程度对脑脉管系统的结构和功能完整性有显著影响。视网膜是大脑的延伸，因此，视网膜血管特征的变化可能是 AD 脑血管病理学的标志物。然而，区分正常衰老与 AD 引起的视网膜血管变化尚未解决。因此，我们比较并量化了年轻、中年和老年三转基因 AD 小鼠模型（3xT-AD）与年龄匹配的对照组（C57BL/6j）的浅层（SVP）、中间（IVP）和深层（DVP）视网膜血管丛的变化。我们使用免疫染色结合一种新的组织光学清除方法以及一种用于定量分析 SVP、IVP 和 DVP 血管网络变化（血管长度和密度）的计算工具。在年轻的 3xTg-AD 和对照组动物中，所有三层都具有相似的结构特征和密度。在对照组中，IVP 和 DVP 密度随年龄增长而降低（从年轻到老年降低 14%至 32%，p<0.05），而 SVP 则没有变化。相比之下，在转基因组中，所有三层的血管参数都随年龄增长而降低（从年轻到老年降低 12%至 49%，p<0.05）。此外，在老年组中，与年龄匹配的对照组相比，转基因动物的 SVP 和 DVP 血管参数较低（p<0.05）。我们的分析表明，正常衰老和 AD 的进展导致视网膜血管发生不同程度的改变。具体来说，与正常衰老相比，AD 进展过程中 SVP 和 DVP 区域的血管特征变化加速。考虑到最近在视网膜毛细血管网络和微血管成像的深度分辨成像领域的进展，非侵入性定量监测 SVP 和 DVP 视网膜血管网络参数的变化可能成为 AD 诊断和分期的标志物，并区分 AD 引起的血管衰减与与年龄相关的血管病变。
