Dikranian Krikor, Kim Jungsu, Stewart Floy R, Levy Marilyn A, Holtzman David M
Department of Anatomy and Neurobiology, Washington University in Saint Louis, MO 6311, USA.
Int J Clin Exp Pathol. 2012;5(6):482-95. Epub 2012 Jul 29.
Alzheimer's disease is characterized in part by extracellular aggregation of the amyloid-β peptide in the form of diffuse and fibrillar plaques in the brain. Electron microscopy (EM) has made an important contribution in understanding of the structure of amyloid plaques in humans. Classical EM studies have revealed the architecture of the fibrillar core, characterized the progression of neuritic changes, and have identified the neurofibrillary tangles formed by paired helical filaments (PHF) in degenerating neurons. Clinical data has strongly correlated cognitive impairment in AD with the substantial synapse loss observed in these early ultrastructural studies. Animal models of AD-type brain amyloidosis have provided excellent opportunities to study amyloid and neuritic pathology in detail and establish the role of neurons and glia in plaque formation. Transgenic mice overexpressing mutant amyloid precursor protein (APP) alone with or without mutant presenilin 1 (PS1), have shown that brain amyloid plaque development and structure grossly recapitulate classical findings in humans. Transgenic APP/PS1 mice expressing human apolioprotein E isoforms also develop amyloid plaque deposition. However no ultrastructural data has been reported for these animals. Here we show results from detailed EM analysis of amyloid plaques in APP/PS1 mice expressing human isoforms of ApoE and compare these findings with EM data in other transgenic models and in human AD. Our results show that similar to other transgenic animals, APP/PS1 mice expressing human ApoE isoforms share all major cellular and subcellular degenerative features and highlight the identity of the cellular elements involved in Aβ deposition and neuronal degeneration.
阿尔茨海默病的部分特征是大脑中淀粉样β肽以弥漫性和纤维状斑块的形式在细胞外聚集。电子显微镜（EM）在理解人类淀粉样斑块的结构方面做出了重要贡献。经典的电子显微镜研究揭示了纤维状核心的结构，描述了神经突变化的进展，并确定了退化神经元中由双螺旋丝（PHF）形成的神经原纤维缠结。临床数据强烈表明，AD中的认知障碍与这些早期超微结构研究中观察到的大量突触丧失密切相关。AD型脑淀粉样变性的动物模型为详细研究淀粉样蛋白和神经突病理学以及确定神经元和神经胶质细胞在斑块形成中的作用提供了绝佳机会。单独过表达突变淀粉样前体蛋白（APP）或同时过表达突变早老素1（PS1）的转基因小鼠表明，脑淀粉样斑块的发展和结构大致概括了人类的经典发现。表达人类载脂蛋白E异构体的转基因APP/PS1小鼠也会出现淀粉样斑块沉积。然而，尚未报道这些动物的超微结构数据。在这里，我们展示了对表达人类ApoE异构体的APP/PS1小鼠淀粉样斑块进行详细电子显微镜分析的结果，并将这些发现与其他转基因模型和人类AD的电子显微镜数据进行了比较。我们的结果表明，与其他转基因动物类似，表达人类ApoE异构体的APP/PS1小鼠具有所有主要的细胞和亚细胞退行性特征，并突出了参与Aβ沉积和神经元变性的细胞成分的特征。
