Intracellular accumulation of toxic turn amyloid-β is associated with endoplasmic reticulum stress in Alzheimer's disease.
Intracellular accumulation of toxic turn amyloid-β is associated with endoplasmic reticulum stress in Alzheimer's disease.
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DOI：
10.2174/156720513804871372
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发表时间：
2013
影响因子：
2.1
通讯作者：
N. Soejima;Y. Ohyagi;Norimichi Nakamura;E. Himeno;K. Iinuma;N. Sakae;R. Yamasaki;T. Tabira;K. Mur
中科院分区：
文献类型：
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作者：
N. Soejima;Y. Ohyagi;Norimichi Nakamura;E. Himeno;K. Iinuma;N. Sakae;R. Yamasaki;T. Tabira;K. Mur
淀粉样蛋白-β蛋白(A-β)在阿尔茨海默病(AD)患者的早期神经元中积聚。最近，我们发现在阿尔茨海默病(AD)脑内神经元中有一种在22位和23位发生毒性转折的β。在这里，我们研究了Aβ、毒性Aβ和高分子量Aβ寡聚体在早老素1(PS1)基因转导的SH-SY5Y细胞以及3xTg-AD小鼠和AD患者的脑中的积累。免疫组织化学染色显示，G384A和I143T突变型pS1基因可促进TURN Aβ的蓄积，与Aβ前体蛋白(AβPP)基因共转染细胞可进一步促进其积聚。相反，在突变的PS1细胞中，高相对分子质量Aβ寡聚体的积累被促进，但通过与AβPP基因共转染细胞而减弱。在3月龄的3xTg-AD小鼠的神经元中检测到有毒的β，当小鼠的认知能力没有受到损害时。相比之下，在记忆障碍明显的7个月大小鼠的神经元中检测到了高相对分子质量的Aβ寡聚体。此外，免疫染色和免疫印迹显示，在突变的PS1细胞中，Rab4、Rab6和GRP78的表达水平增加，并在3xTg-AD小鼠的神经元中积累。值得注意的是，GRP78免疫反应在2个月龄时增强。AD脑的双标记免疫组织化学染色显示，毒性的Turn Aβ与内质网(ER)应激标志物GRP78明显相关。毒性神经元内TURN Aβ的蓄积可能与早期AD模型小鼠和AD患者脑内ER应激有关。
Amyloid-β protein (Aβ) accumulates in the neurons of Alzheimer's disease (AD) patients at an early stage of the disease. Recently, we found that Aβ with a toxic turn at positions 22 and 23 accumulates in neurons in AD brain. Here, we studied the accumulation of Aβ, toxic turn Aβ and high-molecular-weight Aβ oligomers in presenilin 1 (PS1) gene-transfected SH-SY5Y cells as well as in the brains of 3xTg-AD mice and AD patients. Immunostaining revealed that accumulation of toxic turn Aβ was promoted in G384A- and I143T-mutant PS1-transfected cells and further enhanced by co-transfection of cells with the Aβ-precursor protein (AβPP) gene. In contrast, accumulation of high-molecular-weight Aβ oligomers was promoted in mutant PS1 cells but attenuated by co-transfection of cells with the AβPP gene. Toxic turn Aβ was detected in the neurons of 3xTg-AD mice aged 2 months, when the mice were cognitively unimpaired. In contrast, high-molecular-weight Aβ oligomers were detected in the neurons of 7-month-old mice, when memory dysfunction is apparent. Furthermore, immunostaining and western blotting for Rab4, Rab6 and GRP78 revealed increased levels of these proteins in mutant PS1 cells and their accumulation in the neurons of 3xTg-AD mice. Remarkably, GRP78 immunoreactivity was increased at 2 months of age. Double-label immunostaining of AD brain revealed an apparent association between toxic turn Aβ and GRP78, an endoplasmic reticulum (ER) stress marker. Intraneuronal accumulation of toxic turn Aβ may be associated with ER stress in the brains of AD model mice and AD patients at an early stage.