Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Neurobiol Aging. 2018 Dec;72:40-52. doi: 10.1016/j.neurobiolaging.2018.07.020. Epub 2018 Aug 6.
There is vast knowledge on pathogenic mechanisms in Alzheimer's disease but very little on means by which the brain protects itself from disease. A major candidate in providing neuroprotection is the resident brain neural precursor/stem cell (NPC) pool. Transplanted NPCs possess powerful immune-modulatory and trophic properties in vivo and in vitro, underscoring the question whether resident brain NPCs have any role in regulating disease pathology in Alzheimer's disease, and particularly whether they fail to protect the brain from degeneration. To evaluate brain NPC function in relation to disease pathology, we first characterized the pathological properties of 5xFAD transgenic mouse model of Alzheimer's disease at different ages. We found that age 7 months is a critical time point of heavy amyloid deposition and gliosis but before neurodegeneration and a normal basal rate of NPC turnover in the subventricular zone (SVZ) of 5xFAD mice as compared to wild-type mice. Analysis of NPC functional properties showed that despite preserved rate of turnover, there was substantial SVZ NPC dysfunction as indicated by both ex vivo and in vivo assays. Freshly isolated NPCs from 7-month-old 5xFAD mice exhibited reduced expansion rate and diminished immune-modulatory and trophic properties. Moreover, there was slowed recovery of SVZ NPCs after cytosine-arabinoside insult and markedly reduced migratory response following a lysolecithin-induced lesion in the corpus callosum in vivo. Importantly, these functions were fully preserved in 2-month-old 5xFAD mice, a time point before Alzheimer's disease-specific pathological changes. There was reduced expression of key genes involved in NPC proliferative and migratory response in NPCs derived from 7-month-old 5xFAD mice. The dysfunctional properties and downregulation of gene expression were reversible in NPCs derived from 7-month-old 5xFAD mice following in vitro expansion and were reproduced in wild-type NPC by addition of amyloid beta peptide. Thus, there is age-dependent acquired NPC dysfunction, with loss of immune-modulatory and neurotrophic properties, which is induced by the pathological Alzheimer's brain environment at a critical time point before neurodegeneration. We suggest that failure of resident NPC to provide tissue support may be involved in promoting neurodegeneration.
阿尔茨海默病的发病机制已有大量研究，但大脑如何防止自身患病的机制却知之甚少。为大脑提供神经保护的一个主要候选物是驻留的脑神经前体细胞/干细胞（NPC）池。在体内和体外，移植的 NPC 具有强大的免疫调节和营养特性，这突出了一个问题，即驻留的脑 NPC 是否在调节阿尔茨海默病的疾病病理学方面发挥任何作用，特别是它们是否不能保护大脑免受退化。为了评估与疾病病理学相关的脑 NPC 功能，我们首先在不同年龄的 5xFAD 转基因阿尔茨海默病小鼠模型中描述了其病理特性。我们发现，7 月龄是大量淀粉样蛋白沉积和神经胶质增生的关键时间点，但在神经退行性变之前，5xFAD 小鼠的脑室下区（SVZ）中的 NPC 周转率正常，与野生型小鼠相比。对 NPC 功能特性的分析表明，尽管周转率保持不变，但 SVZ NPC 功能严重障碍，无论是通过体外还是体内检测都可发现。从 7 月龄 5xFAD 小鼠中分离出的 NPC 细胞，其扩增速度降低，免疫调节和营养特性减弱。此外，SVZ NPC 在胞嘧啶阿拉伯糖苷损伤后的恢复速度较慢，并且在体内卵磷脂诱导的胼胝体损伤后的迁移反应明显减少。重要的是，这些功能在 2 月龄的 5xFAD 小鼠中完全保留，此时是出现阿尔茨海默病特异性病理变化之前的时间点。7 月龄 5xFAD 小鼠来源的 NPC 中与 NPC 增殖和迁移反应相关的关键基因表达减少。在体外扩增后，7 月龄 5xFAD 小鼠来源的 NPC 中功能障碍和基因表达下调是可逆的，并且在野生型 NPC 中加入淀粉样β肽后可重现。因此，在神经退行性变之前的关键时间点，NPC 出现了与年龄相关的获得性功能障碍，丧失了免疫调节和神经营养特性，这是由病理性阿尔茨海默病大脑环境诱导的。我们认为，驻留 NPC 无法提供组织支持可能与促进神经退行性变有关。
