Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
J Neurosci Res. 2020 Oct;98(10):1905-1932. doi: 10.1002/jnr.24672. Epub 2020 Jun 18.
In Alzheimer's disease, amyloid plaque formation is associated with the focal death of oligodendrocytes and soluble amyloid β impairs the survival of oligodendrocytes in vitro. However, the response of oligodendrocyte progenitor cells (OPCs) to early amyloid pathology remains unclear. To explore this, we performed a histological, electrophysiological, and behavioral characterization of transgenic mice expressing a pathological form of human amyloid precursor protein (APP), containing three single point mutations associated with the development of familial Alzheimer's disease (PDGFB-APP , also known as J20 mice). PDGFB-APP transgenic mice had impaired survival from weaning, were hyperactive by 2 months of age, and developed amyloid plaques by 6 months of age, however, their spatial memory remained intact over this time course. Hippocampal OPC density was normal in P60-P180 PDGFB-APP transgenic mice and, by performing whole-cell patch-clamp electrophysiology, we found that their membrane properties, including their response to kainate (100 µM), were largely normal. However, by P100, the response of hippocampal OPCs to GABA was elevated in PDGFB-APP transgenic mice. We also found that the nodes of Ranvier were shorter, the paranodes longer, and the myelin thicker for hippocampal axons in young adult PDGFB-APP transgenic mice compared with wildtype littermates. Additionally, oligodendrogenesis was normal in young adulthood, but increased in the hippocampus, entorhinal cortex, and fimbria of PDGFB-APP transgenic mice as pathology developed. As the new oligodendrocytes were not associated with a change in total oligodendrocyte number, these cells are likely required for cell replacement.
在阿尔茨海默病中，淀粉样斑块的形成与少突胶质细胞的局灶性死亡有关，可溶性淀粉样 β 在体外可损害少突胶质细胞的存活。然而，少突胶质前体细胞（OPC）对早期淀粉样病理学的反应仍不清楚。为了探索这一点，我们对表达一种病理性人类淀粉样前体蛋白（APP）的转基因小鼠进行了组织学、电生理学和行为学特征分析，该蛋白包含与家族性阿尔茨海默病（PDGFB-APP，也称为 J20 小鼠）发展相关的三个单点突变。PDGFB-APP 转基因小鼠在断奶后存活率降低，2 个月时表现出过度活跃，6 个月时出现淀粉样斑块，但在此期间其空间记忆保持完整。PDGFB-APP 转基因小鼠 P60-P180 时海马 OPC 密度正常，通过全细胞膜片钳电生理学检测，我们发现其膜特性，包括对海人藻酸（100μM）的反应，基本正常。然而，在 P100 时，PDGFB-APP 转基因小鼠海马 OPC 对 GABA 的反应增强。我们还发现，与野生型同窝仔鼠相比，年轻成年 PDGFB-APP 转基因小鼠海马轴突的郎飞结较短，连接节较长，髓鞘较厚。此外，在年轻成年时，PDGFB-APP 转基因小鼠的少突胶质细胞生成正常，但随着病理的发展，在海马体、内嗅皮层和穹窿中增加。由于新的少突胶质细胞与总少突胶质细胞数量的变化无关，这些细胞可能需要细胞替代。
