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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice
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Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice

机译：羧基末端截短的载脂蛋白E4在转基因小鼠中引起阿尔茨海默氏病样神经变性和行为缺陷

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摘要

Apolipoprotein (apo) E4 increases the risk and accelerates the onset of Alzheimer's disease (AD). However, the underlying mechanisms remain to be determined. We previously found that apoE undergoes proteolytic cleavage in AD brains and in cultured neuronal cells, resulting in the accumulation of carboxyl-terminal-truncated fragments of apoE that are neurotoxic. Here we show that this fragmentation is caused by proteolysis of apoE by a chymotrypsin-like serine protease that cleaves apoE4 more efficiently than apoE3. Transgenic mice expressing the carboxyl-terminal-cleaved product, apoE4(Delta272-299), at high levels in the brain died at 2-4 months of age. The cortex and hippocampus of these mice displayed AD-like neurodegenerative alterations, including abnormally phosphorylated tau (p-tau) and Gallyas silver-positive neurons that contained cytosolic straight filaments with diameters of 15-20 nm, resembling preneurofibrillary tangles. Transgenic mice expressing lower levels of the truncated apoE4 survived longer but showed impaired learning and memory at 6-7 months of age. Thus, carboxyl-terminal-truncated fragments of apoE4, which occur in AD brains, are sufficient to elicit AD-like neurodegeneration and behavioral deficits in vivo. Inhibiting their formation might inhibit apoE4-associated neuronal deficits. [References: 61]
机译：载脂蛋白（apo）E4会增加患病风险，并加速阿尔茨海默氏病（AD）的发作。但是，底层机制仍有待确定。我们以前发现，apoE在AD脑和培养的神经元细胞中经历蛋白水解裂解，导致apoE的羧基末端截短的片段积累，这是神经毒性的。在这里，我们显示这种片段化是由胰凝乳蛋白酶样丝氨酸蛋白酶对apoE的蛋白水解所致，该酶比apoE3更有效地切割apoE4。在大脑中高水平表达羧基末端裂解产物apoE4（Delta272-299）的转基因小鼠在2-4个月大时死亡。这些小鼠的皮质和海马表现出AD样神经退行性改变，包括异常磷酸化的tau（p-tau）和Gallyas银阳性神经元，其中含有直径为15-20 nm的胞质直丝，类似于神经原纤维缠结。表达较低水平的截短的apoE4的转基因小鼠存活时间更长，但在6-7个月大时显示学习和记忆受损。因此，出现在AD脑中的apoE4的羧基末端截短片段足以在体内引起类似AD的神经变性和行为缺陷。抑制它们的形成可能会抑制与apoE4相关的神经元缺陷。 [参考：61]

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