Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice
Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice
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DOI：
10.1073/pnas.1434398100
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发表时间：
2003-09-16
影响因子：
11.1
通讯作者：
Huang, YD
中科院分区：
文献类型：
--
作者：
Harris, FM;Brecht, WJ;Huang, YD
载脂蛋白（apo）E4增加阿尔茨海默病（AD）的风险并加速其发病。然而，其根本机制仍有待确定。我们以前发现，载脂蛋白E在AD大脑和培养的神经元细胞中发生蛋白水解裂解，导致羧基末端截短的载脂蛋白E片段的积累，这些片段具有神经毒性。在这里，我们表明，这种碎片是由蛋白水解的载脂蛋白E的糜蛋白酶样丝氨酸蛋白酶，切割载脂蛋白E4比载脂蛋白E3更有效。在大脑中高水平表达羧基末端切割产物apoE 4（Delta 272 -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显示出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，其含有直径为15-20 nm的胞质直丝，类似于神经元前缠结。表达较低水平的截短型apoE 4的转基因小鼠存活时间更长，但在6-7个月大时表现出学习和记忆受损。因此，羧基末端截短的片段apoE 4，这发生在AD脑，足以引起AD样神经变性和行为缺陷在体内。抑制它们的形成可能会抑制apoE 4相关的神经元缺陷。
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.