Federal Research Center Institute of Cytology and Genetics, Novosibirsk, Russia.
Federal Research Center Institute of Cytology and Genetics, Novosibirsk, Russia.
Exp Gerontol. 2019 Jan;115:32-45. doi: 10.1016/j.exger.2018.11.008. Epub 2018 Nov 8.
Neurogenesis is the key mechanism of neuronal plasticity in the adult mammalian brain. Alterations of neurogenesis happen concurrently with (and contribute to) development and progression of numerous neuropathological conditions including Alzheimer's disease (AD). Being the most common type of dementia, AD is studied extensively; however, the data concerning changes in neurogenesis in the pathogenesis of this disease are inconsistent. Here, using OXYS rats as a suitable model of the most common (sporadic) form of AD, we examined neurogenesis in the hippocampal dentate gyrus in early ontogenesis prior to appearance of any signs of neurodegeneration and during development and progression of AD-like pathology. We demonstrated retardation of hippocampal development in OXYS rats at an early age; this problem may contribute to the emergence of AD signs late in life. Manifestation and progression of AD-like pathology are accompanied by transcriptome changes affecting genes involved in neurogenesis in the hippocampus. These genes are associated with the extracellular matrix and angiogenesis; this observation points to alteration of a cellular microenvironment. This change along with an increased TrkA/p75 ratio of nerve growth factor receptors in the hippocampus may contribute to increased density of immature neurons that we observed at the progressive stage of AD-like pathology in OXYS rats. These changes may be considered a compensatory reaction intended to slow down AD-associated neurodegeneration at the progressive stage of the disease. Collectively, these data suggest that alterations of neurogenesis may not only accompany the course of Alzheimer's disease but also play a causative role in this disorder.
神经发生是成年哺乳动物大脑神经元可塑性的关键机制。神经发生的改变与许多神经病理学状况的发展和进展同时发生（并有助于其发生），包括阿尔茨海默病（AD）。AD 是最常见的痴呆类型，受到广泛研究；然而，关于这种疾病发病机制中神经发生变化的数据并不一致。在这里，我们使用 OXYS 大鼠作为最常见（散发性）AD 形式的合适模型，在出现任何神经退行性病变迹象之前以及在 AD 样病理学的发展和进展过程中，检查了海马齿状回中的神经发生。我们证明了 OXYS 大鼠在早期的海马发育迟缓；这个问题可能导致 AD 症状在生命后期出现。AD 样病理学的表现和进展伴随着影响海马体神经发生的基因的转录组变化。这些基因与细胞外基质和血管生成有关；这一观察结果表明细胞微环境发生了改变。这种变化以及海马体中神经生长因子受体 TrkA/p75 比例的增加，可能导致我们在 OXYS 大鼠 AD 样病理学的进展阶段观察到的未成熟神经元密度增加。这些变化可以被认为是一种代偿性反应，旨在减缓疾病进展阶段与 AD 相关的神经退行性变。总的来说，这些数据表明神经发生的改变不仅可能伴随着阿尔茨海默病的病程，而且可能在这种疾病中起因果作用。
