Institute of Cytology and Genetics, Novosibirsk, Russia.
Siberian State Medical University, Tomsk, Russia.
BMC Genomics. 2018 Feb 9;19(Suppl 3):75. doi: 10.1186/s12864-018-4480-9.
Cerebrovascular dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD): the most common cause of dementia in the elderly. The involvement of neurovasculature disorders in the progression of AD is now increasingly appreciated, but whether they represent initial factors or late-stage pathological changes during the disease is unclear. Using senescence-accelerated OXYS rats, which simulate key characteristics of sporadic AD, we evaluated contributions of cerebrovascular alterations to the disease development. At preclinical, early, and advanced stages of AD-like pathology, in the hippocampus of OXYS and Wistar (control) rats, we evaluated (i) the blood vessel state by histological and electron-microscopic analyses; (ii) differences in gene expression according to RNA sequencing (RNA-Seq) to identify the metabolic processes and pathways associated with blood vessel function; (iii) the amount of vascular endothelial growth factor (VEGF) by western blot and immunohistochemical analysis.
We observed a loss of hippocampal blood vessel density and ultrastructural changes of those blood vessels in OXYS rats at the early stage of AD-like pathology. There were significant alterations in the vessels and downregulation of VEGF with an increased amount of amyloid β there at the advanced stage of the disease. According to RNA-Seq data analysis, major alterations in cerebrovascular processes of OXYS rats were associated with blood vessel development, circulatory system processes, the VEGF signaling pathway, and vascular smooth muscle contraction. At preclinical and early stages of the AD-like pathology, these processes were upregulated and then downregulated with age. At the advanced stage in OXYS rats, differentially expressed genes (DEGs) were associated with downregulation of cerebrovascular function as compared to Wistar rats. Among the 46 DEGs at the preclinical stage of the disease, 28 DEGs at the early stage, and among 85 DEGs at the advanced stage, using functional analysis and gene network construction, we identified genes (Nos1, P2rx4, Pla2g6, and Bdkrb2) probably playing a significant role in the development of cerebrovascular dysfunction in OXYS rats.
Changes in expression of the genes functionally associated with cerebrovascular processes already in the early period of life may contribute to the development of AD-like pathology in OXYS rats.
脑血管功能障碍在阿尔茨海默病（AD）发病机制中起着关键作用：这是老年人最常见的痴呆症病因。现在越来越认识到神经血管紊乱在 AD 进展中的作用，但它们是代表疾病初始因素还是晚期病理变化尚不清楚。使用模拟散发性 AD 关键特征的加速衰老 OXYS 大鼠，我们评估了脑血管改变对疾病发展的贡献。在 AD 样病理的临床前、早期和晚期阶段，我们在 OXYS 和 Wistar（对照）大鼠的海马体中评估了：（i）通过组织学和电子显微镜分析评估血管状态；（ii）根据 RNA 测序（RNA-Seq）确定与血管功能相关的代谢过程和途径的基因表达差异；（iii）通过 Western blot 和免疫组织化学分析评估血管内皮生长因子（VEGF）的含量。
我们观察到 OXYS 大鼠在 AD 样病理早期阶段海马体血管密度降低和血管超微结构改变。在疾病晚期，血管存在明显改变，VEGF 下调，同时有大量淀粉样β存在。根据 RNA-Seq 数据分析，OXYS 大鼠脑血管过程的主要改变与血管发育、循环系统过程、VEGF 信号通路和血管平滑肌收缩有关。在 AD 样病理的临床前和早期阶段，这些过程随着年龄的增长而上调，然后下调。在 OXYS 大鼠的疾病晚期阶段，与 Wistar 大鼠相比，差异表达基因（DEGs）与脑血管功能下调有关。在疾病的临床前阶段有 46 个 DEGs，在早期阶段有 28 个 DEGs，在晚期阶段有 85 个 DEGs，通过功能分析和基因网络构建，我们确定了（Nos1、P2rx4、Pla2g6 和 Bdkrb2）等基因可能在 OXYS 大鼠脑血管功能障碍的发展中发挥重要作用。
在生命早期与脑血管过程功能相关的基因表达变化可能导致 OXYS 大鼠出现 AD 样病理。
