Rudnitskaya E A, Kolosova N G, Stefanova N A
Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
Biochemistry (Mosc). 2017 Mar;82(3):318-329. doi: 10.1134/S0006297917030105.
Alzheimer's disease (AD) is the most common type of age-related dementia. The development of neurodegeneration in AD is closely related to alterations in neurotrophic supplementation of the brain, which may be caused either by disorder of neurotrophin metabolism or by modification of its availability due to changes in the microenvironment of neurons. The underlying mechanisms are not fully understood. In this work, we used senescence-accelerated OXYS rats as a unique model of the sporadic form of AD to examine the relationship of development of AD signs and changes in neurotrophic supplementation of the cortex. Based on comparative analysis of the transcriptome of the frontal cerebral cortex of OXYS and Wistar (control) rats, genes of a neurotrophin signaling pathway with different mRNA levels in the period prior to the development of AD-like pathology in OXYS rats (20 days) and in the period of its active manifestation (5 months) and progression (18 months) were identified. The most significant changes in mRNA levels in the cortex of OXYS rats occurred in the period from 5 to 18 months of age. These genes were associated with neurogenesis, neuronal differentiation, synaptic plasticity, and immune response. The results were compared to changes in the levels of brain-derived neurotrophic factor (BDNF), its receptors TrkB and p75, as well as with patterns of their colocalization, which reveal the balance of proneurotrophins and mature neurotrophins and their receptors. We found that alterations in neurotrophic balance indicating increased apoptosis precede the development of AD-like pathology in OXYS rats. Manifestation of AD-like pathology occurs against a background of activation of compensatory and regenerative processes including increased neurotrophic supplementation. Active progression of AD-like pathology in OXYS rats is accompanied by the suppression of activity of the neurotrophin system. Thus, the results confirm the importance of the neurotrophin system as a potential target for development of new approaches to slow age-related alterations in brain and AD development.
阿尔茨海默病（AD）是最常见的与年龄相关的痴呆类型。AD中神经退行性变的发展与大脑神经营养补充的改变密切相关，这可能是由于神经营养因子代谢紊乱或由于神经元微环境变化导致其可用性改变所致。其潜在机制尚未完全明确。在这项研究中，我们使用衰老加速的OXYS大鼠作为散发性AD的独特模型，来研究AD症状的发展与皮质神经营养补充变化之间的关系。基于对OXYS大鼠和Wistar（对照）大鼠额叶皮质转录组的比较分析，确定了在OXYS大鼠出现AD样病理之前（20天）、其活跃表现期（5个月）和进展期（18个月）具有不同mRNA水平的神经营养因子信号通路基因。OXYS大鼠皮质中mRNA水平的最显著变化发生在5至18月龄期间。这些基因与神经发生、神经元分化、突触可塑性和免疫反应相关。将结果与脑源性神经营养因子（BDNF）及其受体TrkB和p75的水平变化以及它们的共定位模式进行比较，这些共定位模式揭示了前体神经营养因子和成熟神经营养因子及其受体的平衡。我们发现，在OXYS大鼠中，表明细胞凋亡增加的神经营养平衡改变先于AD样病理的发展。AD样病理的表现是在包括神经营养补充增加在内的代偿和再生过程激活的背景下发生的。OXYS大鼠中AD样病理的活跃进展伴随着神经营养因子系统活性的抑制。因此，结果证实了神经营养因子系统作为开发减缓大脑与年龄相关变化及AD发展新方法的潜在靶点的重要性。
